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Review Article

A Guide to the Postmortem Investigation of Starvation in Adults

Garland, Jack BMed; Irvine, Rebecca MD, FRCPA, IFCAP

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The American Journal of Forensic Medicine and Pathology: September 2022 - Volume 43 - Issue 3 - p 205-214
doi: 10.1097/PAF.0000000000000763
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Abstract

Starvation is rare in developed countries and shows great regional inequality worldwide. The prevalence of undernourishment (inability to meet the daily minimum dietary energy requirements, for a period of 1 year) in 2020 ranged from approximately 24.1% in Sub-Saharan Africa to less than 2.5% in most developed countries.1 Although starvation worldwide is associated with food insecurity and poverty,2 starvation in developed countries is particularly associated with specific mental illnesses, as well as disease states affecting food consumption.3 Wasting is defined as low weight for height, of which starvation is a known cause, but wasting may also be secondary to acute or chronic illnesses affecting bodily processes such as nutrient absorption and metabolism.4 Although several disease processes are associated with starvation, these must be differentiated from wasting disorders without starvation. Further complicating matters, many wasting disorders may overlap with starvation as well, and weight loss may be secondary to a disorder of metabolism that is also associated with decreased food intake.

In part because of their rarity, the investigation of deaths from starvation remains a challenging area of forensic pathology practice, with limited available guides and surprisingly few advancements from early forensic literature.

In 1903, the “Text-book of Legal Medicine and Toxicology” outlined well the many questions that may be posed in starvation-associated deaths5: (1) “Are the usual appearances of death from starvation present in the body examined?” (2) “Are there evidences of the existence of other diseases present?” (3) “If the latter is the case, could such disease have given rise to the appearances of starvation or to the starvation itself?” (4) “Could such diseases have materially influenced the course of ordinary starvation?” (5) “Are there reasons to believe that the deprivation of food could have caused the lesions of such other discovered diseases, or could it have seriously complicated the course of such affection?” (6) “What relation do the antemortem symptoms, as known or elicited by the legal enquiry, bear to the probability of death by starvation or by other discovered diseases?”5

Although these issues remain as important as they were more than 100 years ago, even contemporary forensic references are limited (with the possible exception of the pediatric population), with few resources for measurement standards, histopathological features, or practical laboratory investigations. Gross pathological findings are often vague, and there is limited advice for the exclusion of nonstarvation causes of wasting, despite references acknowledging the importance of this distinction.3,6,7 Biochemical investigations may be similarly complicated by nonspecific findings and, in some cases, may be pathologically “normal,” as cases of starvation require a unique frame of reference.8

Recent clinical attention to anorexia nervosa, a model for starvation and malnutrition, has provided insight into the physiological and biochemical changes associated with starvation, as well as the mechanisms for death. Although predominantly the product of clinical medicine, this research provides useful information for forensic pathology practice and expected postmortem findings.

In general, there are scant comprehensive forensic pathology resources discussing the approach, findings, and mechanisms of death in cases of suspected starvation. This article aims to provide a summary of the literature on this complex and often overlooked area, and a practical compendium for objective postmortem examination of adult and adolescent starvation cases (pediatrics being a complex area in its own right and not the focus of this review).

CAUSES AND FEATURES

In developed nations, anorexia nervosa has arguably been the most rigorously researched cause of starvation in contemporary literature and serves as a useful model for starvation pathophysiology and diagnostic features. Anorexia nervosa is defined as the restriction of energy intake relative to requirements leading to a significantly low body weight, intense fear of gaining weight, and disturbance in the way in which one's body is experienced.9 The severity of anorexia nervosa is further categorized, when also meeting the previously mentioned criteria, based on body mass index (BMI) into mild (BMI ≥ 17 kg/m2), moderate (BMI of 16–16.99 kg/m2), severe (BMI of 15–15.99 kg/m2), and extreme (BMI < 15 kg/m2).9

Despite a rare lifetime prevalence of approximately 0.1% to 3.6% women and 0% to 0.3% in men, anorexia nervosa carries very high morbidity and mortality.10 There is a standardized mortality ratio of approximately 5.9 times increased risk of death10 as well as increased risk of immunodepression, electrolyte disturbance, endocrine dysfunction, and bone and organ complications.11

As a model for starvation in developed countries, anorexia nervosa has provided useful insight into starvation in general, which includes numerous primary causes (such as neglect or food scarcity), which can be more difficult to uncover or to ethically study. Table 1 lists many important causes of wasting (including starvation-associated and nonstarvation causes), with guidance for differentiating between and excluding these causes.

TABLE 1 - Causes of Wasting and Their Features
Cause Mechanism of Wasting Features and Differentiation
Neglect - Reduction in quantity and quality of nutritional intake
- Metabolic and physiologic effects of underlying untreated/undertreated co-pathologies, if present
- History and scene information are important.
- Careful examination for other types of abuse (sexual, physical)
- Neglect difficult to diagnose, requires underlying decreased capacity for independence (such as age and physical or mental disability)
- May be numerous overlapping medical conditions and risk factors for wasting as well as undernourishment specifically 12
- Pressure ulcers can be a feature and may be independent of neglect. 13
Sarcopenia of older adults - Sarcopenia is not necessarily associated with undernourishment and also occurs in the healthy and well-nourished older adults.
- Loss of muscle mass is multifactorial (inflammation, mitochondrial abnormalities, decreased oral intake, loss of neuromuscular junctions, and hormonal changes). 14
- Except in (albeit, not uncommon) cases of co-presence of other diseases associated with wasting, primary sarcopenia is isolated loss of muscle mass and changes in other organs should not be present to significant extent.
Chronic alcoholism - Multifactorial (reduction in quantity and quality of nutritional intake, malabsorptive consequences of alcohol and liver disease, and sarcopenic and metabolic effects of alcohol and liver disease) 15 - Clinical history, scene information particularly valuable, as starvation and chronic alcoholism may cause similar pathology (steatohepatitis, ketosis, and pancreatitis)
- The 2 diseases often coexist
- Sequelae of chronic alcoholism relating to severe liver disease such as coagulopathy and hepatic encephalopathy occur rarely in starvation. 16
T1DM (including secondary to nonimmune pancreatic destruction, such as from cystic fibrosis, pancreatitis, and trauma) - Lack of insulin Histology:
- Lymphocyte infiltration and destruction of pancreatic islet cells in early autoimmune T1DM
- In other causes of T1DM, features vary depending on the underlying cause of pancreatic damage.
Biochemistry:
- Low insulin and C-peptide if no recent insulin use (often low in starvation as well)
- Normal to elevated insulin and low C-peptide if recent insulin use
- Elevated blood glucose levels if poor insulin management, and elevated ketones in diabetic ketoacidosis (primary starvation may have elevated ketones, but glucose should not be elevated)
- Glucagon levels often elevated in both T1DM (due to loss of insulin feedback inhibition, despite elevated blood glucose 17 ) and starvation (due to low insulin and blood glucose)
Chronic kidney disease - Multifactorial (inflammatory pathways, increase in protein catabolism, decrease in protein synthesis, insulin resistance, increased metabolism, and decreased appetite) 18 - Renal atrophy and microscopic loss of glomeruli, with renal fibrosis, inflammation, and other histological correlates depending on disease progression
Chronic obstructive pulmonary disease - Multifactorial (inflammatory pathways, muscle disuse, oxidative stress, increased metabolism, protein degradation, and reduced muscle regeneration) 19 - Macroscopic and microscopic features of chronic bronchitis, chronic asthma, emphysema, or rarer causes of COPD
Chronic heart failure - Multifactorial (malabsorption due to gut edema, cytokine production leading to anorexia, decreased oral intake due to fatigue, inflammatory pathways, and increased metabolism) 20 - Features of underlying cause of heart failure (such as hypertension or ischemic heart disease), cardiac chamber dilation, and systemic features depending on type and severity of heart failure such as pulmonary hypertension and cardiac cirrhosis
Rheumatoid arthritis - May often exhibit sarcopenia, without necessarily emaciation, and may even appear obese 21
- Multifactorial (inflammatory pathways, increased metabolism, and reduced oral intake)
- Joint deformity, histological features of synovial inflammation, and evidence of systemic complications including vasculitis and pericarditis
Chronic infections (including AIDS and tuberculosis) - Multifactorial (increased metabolism, decreased oral intake, and sometimes malabsorption) - Disease-specific organ pathology and histological findings, cultures, and/or virology testing
Gastrointestinal pathologies (including inflammatory bowel disease and malabsorptive diseases such as celiac disease) - Multifactorial (malabsorption, inflammatory pathways, and, in some cases, gastrointestinal losses such as bleeding) - Disease-specific organ pathology and histological findings, such as cobblestoning and transmural inflammation in Crohn disease
- Postmortem diagnoses of less-overt diseases such as celiac disease challenging due to autolysis and clinical history can be essential
Other chronic illnesses (including malignancy, chronic liver disease, cystic fibrosis, and other autoimmune and inflammatory diseases) - Disease-dependent multifactorial mechanisms (inflammatory pathways, anorexia, increased metabolism, and sometimes malabsorption) 22 - Disease-specific organ pathology and histological findings
- In the case of malignancies with no antemortem diagnosis, thorough autopsy (including bowel examination) and use of postmortem CT screening may uncover primary and metastatic sites
Other, rare causes (including pheochromocytoma, retroperitoneal fibrosis, pancreatic insufficiency, adrenal insufficiency, etc) - Disease-dependent multifactorial mechanisms - Disease-specific organ pathology and histological findings
- In cases without an antemortem diagnosis, best opportunity for diagnosis is thorough autopsy examination and ancillary investigations guided by history of symptoms
COPD, chronic obstructive pulmonary disease; CT, computed tomography.

Although anorexia nervosa has been the most extensively researched cause of starvation, other non–eating-disorder causes of starvation are not uncommon and may overlap with other nonstarvation wasting processes. Diseases such as alcoholism, cancer, and rheumatoid arthritis are associated with decreased nutritional intake but also have separate nonstarvation mechanisms of wasting (see Table 1). Dementia is well known to be associated with decreased nutritional intake, which results from multifactorial causes, including decreased appetite, difficulty chewing and swallowing, reduced ability to prepare and plan meals, memory impairment, changes to taste, altered sleep patterns and wakefulness, and behavioral changes such as combativeness.23,24

Many of these changes may be also present to varying degrees as part of the normal aging process, even in the absence of dementia.23 Sarcopenia, the decline of skeletal muscle tissue with age, is a common condition in older adults, which is multifactorial. In addition to causes of decreased nutritional intake outlined previously, other nonstarvation causes of wasting are thought to play a role in sarcopenia. These include hormonal changes (particularly declines in insulinlike growth factor-1, testosterone, and estrogen), chronic illnesses, inflammation, mitochondrial abnormalities, and loss of neuromuscular junctions.14 This can make the investigation of possible starvation particularly complicated in older adults, where not only many nonstarvation causes of wasting may be present but also where issues of carer neglect may be raised.

Identifying or excluding the different causes of wasting can be a difficult but important task in the investigation of suspected starvation-associated deaths. Failure to adequately investigate alternative explanations for wasting can lead to wrong diagnoses and missed diagnoses of important pathologies that can have legal or heritable implications. Further complicating the investigation of an underlying cause is that many potential causes have overlapping pathological features (such as alcoholic steatohepatitis and nonalcoholic steatohepatitis due to starvation).

Similarly, many causes may exist in the same individual, such as the complex array of pathologies in older adults, where numerous chronic diseases may be present, some of which may also lead to reduced appetite or capacity for self-care. In a typically younger age group, type 1 diabetes mellitus and inflammatory bowel disease are associated with a higher incidence of eating disorders in addition to their pathophysiological risks for wasting.25,26 It is therefore essential that a thorough medical history be sought in addition to rigorous autopsy examination, so that causes of wasting may be confirmed or excluded. Where an inadequate food intake (ie, starvation) cause of wasting is identified, other potential concomitant causes of wasting should still be investigated for (such as reduced food intake in a chronic alcoholic who gets most of their calories from alcohol or reduced oral intake secondary to nausea in a person with terminal cancer).

Relevant Medical and Social History

In addition to the history of concomitant medical conditions that may cause wasting, as discussed previously and outlined in Table 1, other information is also useful in the postmortem investigation of possible starvation. The relevance of this information will vary from case to case, depending on issues such as the age and cognitive status of the patient. Information should be sought on the onset, duration, and progression of weight loss (including weight charts, if available); associated symptoms; and events occurring at or around onset of period of weight loss.27,28 Antemortem investigations of weight loss, including allied health assessments and pathology and radiology testing, should be reviewed, if performed.

Information should be gathered on nutritional history, if available, including food intake and risk factors for decreased food intake, including issues of dentition, swallowing, and neuropsychological issues such as dementia.29 Where mobility or self-care issues are identified, relevant history includes the extent of these issues, home or institutional health care supports, presence or absence of a carer, and the extent of carer role.29,30 Particularly, but not exclusively, in cases requiring carer or nursing home support, consideration should be had for possible neglect and other forms of abuse.30 Relevant history in such cases includes careful review of medical records for previous presentations, as well as home environment circumstances (if scene information available from the home) such as hygiene and access to required medical supports (including physical aids and dentures) and medications.30

Mechanisms of Wasting

While various causes of wasting and their features are outlined in Table 1, the mechanisms behind these causes are discussed here. Although the mechanism of wasting in starvation is comparatively straightforward, being secondary to reduced intake of nutrients, the mechanisms of wasting in nonstarvation causes of wasting can be more complex. As previously discussed, many nonstarvation causes of wasting may also concomitantly present with a lack of adequate food intake (starvation) cause of wasting. In addition, many nonstarvation causes of wasting may have multiple and overlapping mechanisms of wasting.

Chronic inflammation is a common mechanism of wasting shared by many disease processes outlined in Table 1, including chronic kidney disease, chronic obstructive pulmonary disease, malignancy, and autoimmune diseases. Inflammatory cytokines released as part of chronic inflammatory processes cause wasting through multiple pathways, including increased protein turnover, inhibition of muscle differentiation, increased catabolism, and dysregulation of reparative processes for skeletal muscle.31,32

Increased metabolic demands such as occurring in cases of advanced cancer, chronic autoimmune diseases, and chronic infectious processes cause wasting through increased energy requirements in excess of the person's normal basal metabolic rate.33 There is often overlap with inflammation, and inflammatory cytokines such as C-reactive protein can also cause direct hypercatabolic effects.33

Malabsorption, such as occurs in inflammatory bowel disease, celiac disease, pancreatic damage, and even heart failure (if gastrointestinal edema is present), causes weight loss through inadequate absorption of nutrients, even if there is normal food intake.34,35 Although not directly related to malabsorption, inability to use nutrients as a source of energy after absorption (such as occurring because of lack of insulin in type 1 diabetes mellitus) can also lead to wasting.36

Mechanisms of Death

There are numerous potential mechanisms of death in starvation, many of which may compound one another. By the very nature of starvation, limited available energy can result in hypoglycemia, although this is often only seen in advanced stages, where there is underlying liver failure and depletion of resources for glucose production.37,38

Cardiovascular pathologies are one of the most common lethal complications of starvation and can occur as a result of the multifactorial effects of starvation on the body. These effect pathways include dysfunction of multiple neuroendocrine axes (including the hypothalamic-pituitary-gonadal axis, hypothalamic-pituitary-adrenal axis, and hypothalamic-pituitary-thyroid axis), autonomic nervous system dysfunction (including cardiac vagal regulation and sympathetic vascular regulation), and inflammatory cytokines.39,40 Electrolyte disturbances may increase the risk of cardiac arrythmia, and QT prolongation is also a known complication of starvation.8,38,41 Structural cardiac changes in starvation (discussed in greater detail under the section “Organ-Specific Gross and Microscopic Features”) including decreased heart mass and valvular prolapse also increase the risk of sudden cardiac death.11,38

Refeeding syndrome, a complication of treatment of starvation, is characterized by metabolic and electrolyte abnormalities, particularly hypophosphatemia, hypokalemia, and hypomagnesemia.8 When refeeding commences, production of adenosine triphosphate for energy (as well as the effects of insulin and use of phosphate for protein synthesis) causes a decrease in plasma phosphate.8 Refeeding syndrome has a high risk of mortality and is associated with liver injury, cardiac failure, respiratory failure, and neuromuscular dysfunction.8,40 Hypoglycemic coma has been also been reported in cases of acute liver injury induced by nutrient therapy for anorexia nervosa.42,43 Refeeding syndrome is diagnosed clinically as “severely low-serum electrolyte concentrations, fluid and electrolyte imbalance and disturbance of organ function resulting from over-rapid or unbalanced nutrition support,” although an additional criterion of acute circulatory fluid overload has been proposed.44 Symptoms are often nonspecific, and as refeeding syndrome usually occurs in the context of in-hospital treatment, careful monitoring of fluid and electrolyte status is important for diagnosis, as well as ideally to prevent the occurrence of refeeding syndrome in the first place.44

Although not directly a result of starvation, suicide is also a common manner of death in cases of eating disorder–associated starvation and is the manner of death in approximately 1 in 5 deaths in patients with anorexia nervosa.45

Gross Physical Appearances and Anthropometrics

One of the first scientific attempts to investigate the effects of starvation was the Minnesota experiment in 1944. With more than 20 million people dying from starvation during World War II (more than military deaths, at 19.5 million), more scientific information was needed about starvation and its effects on the body. Thirty-six healthy young male volunteers participated, who were conscientious objectors to World War II.46,47 The experiment encompassed a 6-month period of calorie restriction semistarvation, and investigations examined weight, size, appearance, and basic life functions. Although contemporary research, predominantly on anorexia nervosa, has advanced our understanding of the pathophysiological processes in starvation, general physical descriptions have not changed greatly since those outlined in the Minnesota experiment.

Although the gross appearances of starvation may vary depending on factors such as individual variation, concomitant disease processes, and baseline body habitus, there are numerous physical features that are often present. These include decrease in adipose tissue; sunken eyes and abdomen; protruding bony prominences (especially ribs, vertebrae, iliac crests, scapulae, and occiput); skeletal muscle atrophy; pressure sores; brittle nails and hair; pigmented, dry, inelastic, and hyperkeratotic skin; and edema (particularly of the ankles).3,48,49 Features such as sunken eyes and reduced skin turgor may be seen in concomitant dehydration, although in cases of eating disorder–associated starvation, there may actually be excess water consumption, due to the calorie-free nature of water.8 Further externally visible features of starvation are outlined in Table 2.

TABLE 2 - Organ-Specific Gross and Microscopic Features in Starvation
Organ Gross and Microscopic (Including Recommended Special Stains) Features
Heart 11,38,40,65–67 - Decrease in left ventricle mass and volume
- Reduced interventricular septum thickness
- Mitral valve prolapse (thought secondary to myocardial mass changes and subsequent valvuloventricular disproportion)
- Tortuosity of the coronary arteries (thought secondary to myocardial mass changes)
- Features of heart failure, such as edema and pericardial effusion
- Takotsubo cardiomyopathy (thought to be catecholamine mediated), requiring relevant clinical history, and with potential, but nonspecific postmortem features of ventricular dilation and thinning, myocardial edema, and interstitial mononuclear infiltrates
- Histopathology showing vacuolar degeneration, myocardium attenuation, lipofuscin accumulation in the myocardium (Schmorl method stain), moderate interstitial fibrosis (Masson's trichrome stain)
Liver 16,68,69 - Fatty liver
- Histopathology showing steatosis (Oil Red O stain), decreased glycogen stores (periodic acid–Schiff stain and electron microscopy), and no/rare necrosis and apoptosis, but numerous autophagosomes and low organelle density on electron microscopy
Gastrointestinal tract 3,6,40 - Gastric dilation
- Empty gastrointestinal tract
- Dehydrated feces
- Distended gall bladder
- Pseudomelanosis coli (laxative abuse)
- Barrett's esophagus and adenocarcinoma (esophageal acid damage if induced vomiting)
- Mallory-Weiss syndrome esophageal tears (induced vomiting)
Pancreas 70–72 - Atrophy and fatty change
- Histology showing dilatation of small ducts, pancreatic fibrosis (Masson's trichrome stain), and sometimes pancreatitis
- Exocrine pancreas showing reduction in cytoplasm, decreased numbers of mitochondria, and increased lysosomal activity on electron microscopy
Renal tract 59,73 - Renal stones (secondary to cases of low urine output, paradoxical aciduria from cases of vomiting and diuretic or laxative abuse, and recurrent urinary tract infections)
- Nephrocalcinosis
- Renal cysts
- Hypovolemia and electrolyte (particularly hypokalemia) disturbances leading to hypertrophy of the juxtaglomerular apparatus, glomerular sclerosis, interstitial nephritis, and fibrosis (Masson's trichrome stain)
- Hypoperfusion and rhabdomyolysis (myoglobin stain) may show acute tubular injury.
Brain 74,75 - Gray and white matter atrophy
- Ventricular enlargement
- Features of Wernicke-Korsakoff syndrome such as atrophy of the thalamus, hypothalamus, and mammillary bodies may be present in cases of thiamine deficiency.
- Central chromatolysis in cases of pellagra (niacin deficiency)
Musculoskeletal and adipose 59,76,77 - Decreased bone mineral density and osteoporosis
- Increased propensity for fractures, including spinal compression fractures
- Reduced muscle mass
- Rhabdomyolysis secondary to hypokalemia and hypophosphatemia
- Decreased intra-abdominal and abdominal wall fat
- Sunken/scaphoid abdomen
Skin 48,78 - Pressure sores and poor wound healing
- Lanugo body hair (secondary to hypothyroidism)
- Hair loss
- Hyperpigmentation
- Edema
- Dry skin and mucous membranes
- Striae distensae
- Dermatitis, including seborrhoeic dermatitis (scaly red patches predominantly of the face and scalp), acrodermatitis enteropathica in cases of zinc deficiency (scaly erythematous plaques predominantly of the face and anogenital area), and pellagra dermatitis in cases of niacin deficiency (bilateral hyperpigmented rash limited to sun-exposed sites)
- Carotenoderma (secondary to low-calorie carotinoid-rich vegetables and reduced liver conversion of carotene)
- Paronychia
- Petechiae and purpura (vitamins C and K deficiency)
- Rough, “goose skin” appearance (vitamin A deficiency)
- Abrasions and lacerations of knuckles (induced vomiting)
Hematopoetic 48,79,80 - Bone marrow atrophy, hypocellularity, and serous/gelatinous transformation
- Anemia (iron, B12, and folate deficiency)
- Spleen, lymph node, and thymus involution
- Leukopenia
- Thrombocytopenia
Oral cavity 81,82 - Bleeding gums and delayed healing (vitamin C deficiency)
- Cracked lips, gingivitis, and ulcers (deficiency of B vitamins)
- Dental erosion, caries, and sialadenosis (induced vomiting)
Endocrine organs 39,62,83 - Endocrinological testing relating to hypothalamic-pituitary-adrenal axis, hypothalamic-pituitary-gonadal axis, and hypothalamic-pituitary-thyroid axis dysfunction is discussed under the section “Ancillary Laboratory Investigations”
- Physical features of hypothalamic-pituitary-gonadal axis dysfunction: reduced bone mineral density, reduced endometrial thickening, amenorrhea, and accelerated uterine atherosclerosis
- Physical features of hypothalamic-pituitary-thyroid axis dysfunction: atrophy of the thyroid, lanugo body hair, and features of heart failure (see “Heart”)
- Physical features of hypothalamic-pituitary-adrenal axis dysfunction: reduced bone mineral density and muscle wasting. Despite high cortisol levels, features of Cushing syndrome are not typical due to cortisol resistance and low baseline levels of fat.
- Physical features of pituitary dysfunction: edema and renal dysfunction (see “Renal tract”) secondary to excess antidiuretic hormone secretion and short height secondary to increased growth hormone resistance (if starvation started during or before puberty)

Quantifiable classifications of gross physical features of starvation have been devised, which have been used to varying extents in both resource-limited settings and well-resourced dedicated health units in developed countries. Mid–upper arm circumference is a common anthropometric marker of undernourishment in resource-limited settings, with broad cutoffs for underweight status of less than 23 cm in men and22 cm or less in women.50 Mid–upper arm circumference is not restricted to these settings, however, and has been used in combination with triceps skinfold thickness in developed countries to accurately estimate body fat percentage, even compared with dual-energy x-ray absorptiometry.51

Body mass index is the most common quantitative medical tool for estimating body fat in developed countries and uses body weight and height. Under BMI classifications, underweight is less than 18.5 kg/m2 and severely underweight is less than 16.5 kg/m2.52 Although different cutoff levels for overweight and obese have been proposed for different racial groups, in particular Asians, the World Health Organization uses the same cutoff for underweight of less than 18.5 kg/m2 for Asian populations.53,54 Despite its practicality, BMI has nonetheless been criticized for its accuracy and, when used in isolation, may mask body composition abnormalities such as edema and degree of muscle mass.55 Like all anthropometric measures, therefore, BMI must not be interpreted in isolation. In fact, in clinical medicine, the “subjective global assessment” uses a combination of patient symptoms and qualitative physical examination findings (such as edema and muscle wasting) to derive an overall score to determine the need for nutritional intervention, although the postmortem applications of such a tool are likely to be limited.51

Organ-Specific Gross and Microscopic Features

One of the changes that remains constant across nearly all organs in starvation is a general decrease in organ weight. Published information on cutoffs for organ weights in starvation are scant, although numerous publications have established ranges for expected organ weights based on sex, weight, and height. As with all the features of starvation, low organ weights should not be interpreted in isolation, and nor are they specific for starvation as a cause of wasting. Other than atrophy, almost every organ has gross and microscopic changes that may occur in starvation. As discussed in Table 1, many of these changes are nonspecific and are of greatest value in combination and with the exclusion of nonstarvation causes of wasting. These changes are outlined for each organ in Table 2, but several of the important aspects are summarized here. Select example images of macroscopic and microscopic features that may be seen in starvation are shown in Figures 1 and 2, respectively.

F1
FIGURE 1:
Macroscopic photographs of example features that may be seen in cases of starvation. A, Gaunt face with temporalis muscle atrophy and decreased periocular fat. B, Wasting with decreased fat and muscle mass. C, Decreased mesenteric fat. D, Tortuous coronary arteries. E, Atrophy of abdominal wall fat and intra-abdominal fat. F, Mammillary body brown discoloration in Wernicke encephalopathy.
F2
FIGURE 2:
Microscopic photographs of example features that may be seen in cases of starvation. A, Vacuolated cardiac myocytes (×20 hematoxylin and eosin [HE]). B, Atrophy of epicardial fat (“A',” ×20 HE) versus normal epicardial fat for comparison (“N,” ×20 HE). C, Hepatic steatosis (×4 HE). D, Serous atrophy of the bone marrow (×20 HE). E, Central chromatolysis in pellagra (×20 HE).

Although electrolyte and metabolic abnormalities underpin many of the risks of sudden cardiac death in starvation, numerous morphological changes are also present, which are a structural correlate to physiological dysfunction. Mitral valve prolapse secondary to left ventricle atrophy is a cause of the mitral regurgitation that is often present in starvation. Some other organ-based dysfunctions do not show gross or histological correlates in their site of origin but have noticeable effects on other organs. As an example, findings such as lanugo hair and various cardiovascular and renal complications (including takotsubo cardiomyopathy and glomerular sclerosis, respectively) are influenced in part by endocrine dysfunction (see Table 2).

As with any postmortem histopathology, autolysis may be a limiting factor to interpretation, particularly in evaluation of the gastrointestinal tract, pancreas, and kidneys. Although use of special stains such as Masson's trichrome for connective tissue may aid examination, some cases may simply have limited assessable histological information. As outlined where applicable in Table 2, many organ features in starvation are reflective of specific pathologies that are not present in all cases of starvation and/or that may be present in malnutrition without starvation. These include sequelae of specific nutrient deficiencies and some behavioral components of eating disorders, such as purging and diuretic and laxative abuse.

Toxicological Analysis

Toxicological analysis may assist in providing clues for medical history in cases where limited history is available and may also help to investigate possible overdose, given the high rate of suicide, particularly in eating disorder causes of starvation. In addition, physiological and metabolic consequences of starvation on pharmacokinetics make these patients more vulnerable to potential overdose at otherwise “normal” doses of medications through several mechanisms.56 Reduction in body fat and body weight may decrease the volume of distribution of lipophilic drugs in particular, and reduced plasma proteins may cause an increase in unbound drug levels. Reduced drug metabolism and excretion may also contribute to higher peak concentrations of drugs. Cases of eating disorders are also associated with higher rates of alcohol and illicit substance abuse, particularly amphetamines, cocaine, heroin, analgesics, and hallucinogens.57 Diuretics and laxatives can be used as methods of weight loss in patients with eating disorders.36

Ancillary Laboratory Investigations

In addition to clinical history, thorough autopsy examination, and histopathological examination, numerous ancillary investigations have merit in the investigation of starvation.

Biochemical analysis of vitreous humor is expected to not show elevated glucose, although low glucose levels cannot be relied upon postmortem to reflect antemortem concentrations. Ketones are often elevated in starvation as an alternate fuel source and can be sufficiently elevated to constitute a starvation ketoacidosis.58 Alcoholism is a common comorbidity in cases of eating disorder–associated starvation, however, and alcoholic ketoacidosis may coexist with starvation ketoacidosis.58 Because of low muscle mass, creatinine levels are often within normal or low ranges, despite a functionally low glomerular filtration rate, and must be kept in mind when considering renal impairment.8,59

Testing for decreased serum prealbumin levels can be a useful indicator of starvation/undernourishment in the clinical and postmortem settings; however, serum albumin testing is unreliable and may actually be increased in dehydration.29,60 In cases of dehydration, a hypertonic dehydration may be apparent, with elevated sodium, chloride, and urea,3 although in eating disorder–associated starvation, low sodium and chloride may be seen as a result of excess water consumption.8 Other electrolyte changes seen in starvation including low phosphate (with or without refeeding syndrome), magnesium, calcium, and potassium are of most value if antemortem results are available as postmortem changes (particularly for potassium) may impair accurate findings.

Insulin levels in starvation are typically low or normal8 but may be of value to measure in cases of type 1 diabetes mellitus due to the higher rates of eating disorders in this group, often with the deliberate restriction of insulin use.25 Insulin and C-peptide levels are expected to be low in starvation and untreated diabetes, but altered insulin and C-peptide ratio can be useful to assess both prescribed and nonprescribed exogenous insulin administration and overdose. Insulin may also cause appetite suppression, and exogenous insulin administration has been documented as being abused for this purpose.61

Further endocrinological tests can be performed, where indicated, to investigate for alternative explanations of wasting as well as to assess for potential endocrine dysfunction secondary to starvation (see Table 2), including urine adrenaline (elevated in pheochromocytoma) and serum cortisol (decreased in adrenal insufficiency and can be elevated in starvation, in addition to elevated corticotropin-releasing hormone and adrenocorticotropic hormone) and thyroid function tests (elevated in hyperthyroidism and decreased in starvation and hypothyroidism).62,63 Regarding the specific thyroid function test components, cases of starvation may show normal to below-normal thyroid-stimulating hormone levels, low T3 levels, low to normal T4 levels, and low thyrotropin-releasing hormone levels.62

Investigations for infectious causes of wasting can be performed where warranted, including for human immunodeficiency virus, as well as stool sample analysis for parasites such as Giardia and cultures for organisms such as Mycobacterium tuberculosis.3 Postmortem imaging such as computed tomography can be used to guide autopsy examination and ancillary testing, as well as provide useful information on bone density and fractures. Finally, where local facilities allow, isotope analyses of hair have been proposed as a means of assessing chronicity of excess protein and fat catabolism seen in starvation.64

Conclusion

Despite the high mortality risks in starvation and its multifaceted pathophysiology, most of the available resources for the investigation and diagnosis of starvation are clinically focused and emphasize treatments as well as investigations that are of less postmortem utility. Conversely, despite scant postmortem guides to the investigation of starvation, the nature of the autopsy process affords a greater extent of gross and microscopic evaluation than is possible antemortem.

The old questions from the 1903 “Text-book of Legal Medicine and Toxicology” remain as important as ever, as does the forensic pathologist's role in this investigative process. Improved knowledge on the pathophysiology of both starvation and other cachectic diseases mean that more investigations are available to the pathologist. As outlined in this article, there are many features of starvation that must be documented but that are often nonspecific in isolation and must be interpreted in the context of the medical history and the exclusion of other causes. Difficulties remain when more than 1 potential cause of wasting is present, although individual disease features may be useful in assessing the extent and severity of such diseases. In the absence of specific biomarkers for primary starvation, the greatest investigative tools remain a thorough autopsy, clinical history, and ancillary investigations where indicated.

REFERENCES

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Keywords:

starvation; anorexia nervosa; autopsy; forensic pathology; malnutrition; review

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