Ten years ago, a physically fit 23-yr-old white man of Greek ancestry flew from the United Kingdom to Cusco, Peru (11,000 ft. altitude), to trek to Machu Picchu. It was his first trip to a high altitude. After just an hour or two in Cusco, before he began trekking, he suffered a splenic infarction that led to splenectomy. Later, back in the United Kingdom, he learned he had sickle cell trait (SCT). The trekking company decided to offer screening for SCT to all potential high-altitude trekkers. Good idea.
We continue to learn ever more about SCT and the spleen. I cover it here. Also, we learn more about intriguing genes that play dual roles. I cover that too.
Splenic Syndrome in SCT
The “splenic syndrome” in SCT typically follows ascent to at least moderate altitude. A seminal report on this syndrome at mountain altitudes was from Colorado, more than 30 yr ago, emphasizing its occurrence in “nonblack” persons (12). Because Colorado has the highest mean altitude (6800 ft) of all 50 states, a population of 5.5 million, and 57 million visitors a year, it seems to be the epicenter of the splenic syndrome. A recent article on 25 cases is informative (9).
Studied were 25 patients with SCT splenic syndrome seen by Colorado physicians over a 20-yr span (1986 to 2006). Clinical and laboratory data were analyzed. All 25 were males, between ages 4 and 40 yr. Ethnicity was identified for 22, nine African-Americans, nine non-Hispanic whites, and four Hispanics. Sixteen were unaware they had SCT.
Only 3 of the 25 were Colorado residents. All lived at 5280 ft and developed the splenic syndrome after hiking at 9000, 10,000, and 12,000 ft, respectively. Twenty-two resided at sea level and visited Colorado; three developed splenic pain while skiing, whereas the others did not report pain while exercising. Almost all developed pain, however, within 24 h of arrival at peak altitude.
All 25 had left upper quadrant abdominal pain, about half had vomiting and/or mild fever, and one third had a palpable spleen. A computed tomography scan was abnormal in 21 of 22, with splenomegaly, subcapsular hematoma, and/or splenic infarctions. Twenty-two were hospitalized. Most recovered smoothly with conservative therapy at a lower altitude (5280 ft), only five got splenectomy (9).
The authors say their findings confirm previous reports that the splenic syndrome is associated with SCT only in males exposed to moderate to high altitudes. This is not accurate, because a few cases have been in females at altitude, including a white physician skiing in Colorado — initially thought to have a pneumothorax — and an African-American climbing Mt. Fuji (7,13). At least one case has occurred in a young, otherwise healthy African-American female in her hometown, near sea level (2). Most cases, however, have been in males at altitude.
It also should be noted that a major SCT splenic syndrome developed in a healthy 49-yr-old African-American man on a flight from San Diego to Newark (he got splenectomy). This complication of commercial flying seems to be rare, even though at cruising altitudes, most airlines pressurize the cabin equal to an altitude of 5000 to 8000 ft (14). I wonder, however, how often passengers — black or white — with SCT experience mild left upper quadrant “discomfort” and “indigestion” (i.e., mild splenic sickling and congestion) during long airline flights. We physicians should bear this in mind, along with the fact that SCT is “malarial, not racial” — has no direct correlation to skin color.
Why the SCT splenic syndrome is reported more often in whites than blacks is debated, but may be explained by: 1) the demographics of those who vacation or ski in Colorado; 2) selective case finding and reporting; and/or 3) the fact that alpha thalassemia, which slightly lowers the percentage of sickle hemoglobin in each red blood cell in SCT and so lessens sickling complications, is common in blacks but rare in whites. It appears that few with the SCT splenic syndrome have alpha thalassemia (9).
Sickling was a newsmaker in 2009, when Pittsburgh Steeler safety Ryan Clark, who has SCT, was told by his coach to skip the game against the Broncos at mile-high Denver. After Clark played in Denver in 2005, he was diagnosed with a “splenic contusion.” He played in Denver again in 2007, suffered an SCT splenic syndrome, developed an abscess in the infarcted, necrotic spleen, and had a splenectomy, which sidelined him for the remainder of that season.
Splenic syndrome also can pose logistical problems for medical staff on road games, as when a college basketball player from Alabama developed abdominal pain, nausea, and vomiting in Wyoming while practicing for a game. He was sent to an emergency room and diagnosed with gastroenteritis twice in 2 d. On his third visit to the emergency room, he was diagnosed correctly with STC splenic syndrome, hospitalized and treated conservatively for 3 d, and then flown home with supplemental oxygen while on the plane.
Besides pneumothorax and gastroenteritis, initial working diagnoses of SCT splenic syndrome have included pleurisy, “side stitch,” renal colic, and bowel obstruction. The pearl is: Consider splenic syndrome in anyone who develops these clinical features at even moderate altitude. Diagnosed early, it responds to conservative therapy, including descent (5).
To paraphrase songwriter Joni Mitchell, I look at genes from both sides now. Maybe diabetes genes were “thrifty genes” that got our forebears through famines. Maybe hemochromatosis genes — by enhancing iron absorption — enabled our ancestors to compensate faster for blood lost in battle. More and more, research supports the notion that some genes can have mixed effects.
For example, a double dose of the sickle-cell gene causes a disease, sickle cell anemia, but a single dose, SCT, protects against death from malaria. In fact, many red-cell phenotypes common in African-Americans and/or in other populations from other malarial regions of our planet are thought somehow to protect against malaria. These include alpha or beta thalassemia, glucose-6-phosphate dehydrogenase (G6PD) deficiency, pyruvate kinase deficiency, hemoglobin C or E, Duffy-negative blood group, and elliptocytosis or ovalocytosis. Even benign ethnic neutropenia protects against malaria (4).
A parallel to SCT and malaria may explain something about focal segmental glomerulosclerosis (FSGS), the most common primary glomerulopathy causing end-stage renal disease in the United States. FSGS is more common and seems more aggressive in blacks than in whites; two black professional basketball stars suffered from it. Genetic mapping finds a “susceptibility gene” for FSGS on chromosome 22, the gene encoding apolipoprotein L1 (APOL1). Its haplotypes G1 and G2 are under strong selection only in Africa.
What is the parallel to SCT and malaria? APOL1 is a plasma factor that can lyse Trypanosoma brucei brucei, the parasite that causes sleeping sickness. A subspecies of this parasite evolved in Africa, and the G1 and G2 haplotypes are best able to lyse it, so G1 and G2 likely became common by natural selection. G1 and G2 are common in African chromosomes (present in > 30% of African-Americans) but absent in European chromosomes. We need more research, however, to learn how G1 and G2 damage glomerular podocytes to cause FSGS (8).
New research suggests that other genes can dance between beneficial and harmful. Although Sardinians are known for longevity, they have high rates of multiple sclerosis (MS). Genome studies of Sardinians have tied a gene variant to MS. This variant is in the gene that encodes a soluble cytokine known as B-cell activating factor (BAFF). This disease-risk variant gene upregulates humoral immunity by increasing levels of BAFF, B lymphocytes, and immunoglobulins. This variant is common in Sardinia but rare, for example, in northern Europe. The authors believe this BAFF variant came from natural selection, because it protects against malaria, which was endemic in Sardinia until the 1950s. This hypothesis fits with the evidence that plasma levels of BAFF increase in acute malaria and mice that overexpress BAFF are protected from lethal malaria. The proposed evolutionary scenario is that the BAFF gene variant was selected as an adaptive response to malaria, resulting in a present-day risk of autoimmunity (11).
Finally, consider the cons and pros of factor V Leiden (FVL), one of the most common inborn hypercoagulopathies. FVL is a risk factor for deep venous thrombosis (DVT) and pulmonary embolus (PE). I have covered athletes with DVT and/or PE in the face of FVL (6), and in the past few months, I have learned of three football players with FVL and DVT. One of them, Syracuse nose tackle Steven Clark, is in the news at this writing, as he awaits a decision on return to play after suffering DVT above and below a tight knee brace that was applied after a knee injury ended his 2016 season (1).
The FVL allele is common in whites (up to 6%), although it is a risk factor for DVT/PE even in heterozygotes. This has led to speculation about an associated survival advantage exerting a positive selective pressure, for example, by reducing blood loss during childbirth. Indeed, it seems that FVL may lessen blood loss during cardiac surgery (3). Also intriguing as for positive selection, the results of a study of patients with major bacterial infection fit with a mouse model of endotoxemia in suggesting that those heterozygous for FVL are more likely to survive severe sepsis (10). In conclusion, whether it comes to nature or nurture, genes or environment, we face balancing acts, and sometimes it seems, in life and in sport, we dance a fine line.
The author declares no conflict of interest and does not have any financial disclosures.