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JAIDS Journal of Acquired Immune Deficiency Syndromes:
doi: 10.1097/QAI.0b013e3181bb27b1
Letters to the Editor

Cryptogenic Pseudocirrhosis: A New Clinical Syndrome of Noncirrhotic Portal Hypertension (Unassociated With Advanced Fibrosis) That Can Be Detected by Transient Elastography in Patients With HIV

Panos, George MD*; Farouk, Lavanta MD†; Stebbing, Justin MRCP, FRCpath, PhD‡; Holmes, Paul MD*; Valero, Sara MD*; Randell, Paul MD*; Bower, Mark PhD, FRCP*; Gazzard, Brian MD, FRCP*; Anderson, Mike MD§; Nelson, Mark MD*

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*HIV/GUM Directorate, Chelsea and Westminster Hospital, St Stephen's Centre, London, United Kingdom, †Department of Gastroenterology, Imperial College Healthcare NHS Trust, London, United Kingdom, ‡Department of Oncology and Surgery, Imperial College Healthcare NHS Trust, London, United Kingdom, §Department of Gastroenterology, Chelsea and Westminster Hospital, London, United Kingdom

To the Editors:

Chronic liver disease is one of main causes of non-AIDS-related death in HIV-infected patients and transient elastography (TE) is a method validated for following up these individuals against histological staging from liver biopsy. Noncirrhotic portal hypertension has been entitled cryptogenic pseudocirrhosis (CPC). We identify 5 patients with this condition in our cohort of HIV-positive individuals, as evaluated by TE.

From our cohort of 12,165 HIV-positive patients followed at the Chelsea and Westminster Hospital HIV/GUM Directorate, London, United Kingdom, 662 underwent TE between August 2006 and February 2008. The criteria for the diagnosis of CPC was the absence of underlying hepatic disease with 1 or more of the following: (1) abnormal liver function tests (LFTs) for more than 6 months; (2) clinical signs of complications of portal hypertension; (3) endoscopic signs of portal hypertension; and (4) liver biopsy without significant fibrosis in the presence of high liver stiffness values (LSVs) (>7.9 kPa) on TE.

A total of 5 individuals with CPC as measured with TE were identified (Table 1). Although the definition of CPC makes reference to absence of hepatotoxic medications, all patients were receiving highly active antiretroviral therapy and all were treated with didanosine, efavirenz, and tenofovir. Antiretroviral therapy, especially didanosine and nevirapine, have been implicated as etiological factors in the development of noncirrhotic portal hypertension. All 5 individuals had LSVs ≥9.9 kPa normally compatible with significant fibrosis, ≥F2 on the Meta-vir scale or >S3 on the Ishak scale. Histopathological findings are summarized in Table 1; perisinusoidal fibrosis was the common histopathological finding in all patients, with sinusoidal dilatation seen in 4 of 5 cases. Esophageal varices were observed in 4 of 5 cases.

Table 1
Table 1
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Here, we report a series of HIV-positive individuals with CPC detected on TE as evident by high LSVs (in kPa) although liver biopsy did not reveal significant fibrosis (F ≥ 2 or S ≥ 3-4 on the METAVIR and ISHAK scale respectively) or cirrhosis (F = 4 or S = 5-6). After TE in cases with abnormal LFTs and no underlying liver disease, biopsy can provide further information on hepatic venous pressure gradient in addition to histology. A total of 31 cases of CPC-including these data-have been reported in HIV-positive patients; all were documented by histological findings consistent with noncirrhotic portal hypertension. In the majority of these cases,1-7 evidence of portal hypertension if not its complications were confirmed. Although patient 5 here did not have the clinical features of portal hypertension, the histological findings of perisinusoidal fibrosis with sinusoidal dilatation are in keeping with a diagnosis of CPC.

Theoretically, portal hypertension is presinusoidal (portal venopathy).1 In practice, however, findings seem consistent with sinusoidal pathology7-also demonstrated by our histological findings. Mechanisms proposed for the pathogenesis of noncirrhotic portal hypertension implicate primary vasculopathy and alterations in blood flow1 with obliterative changes in portal veins causing reduction in blood flow within the acini.1,2 An abnormal portal space is defined as a portal vein to portal space ratio <0.08.2 CPC is a late diagnosis, as even with biopsy in the early stages it may be labeled as crytogenic liver disease (CLD) unless portal pressure is measured. Hence there is a prolonged asymptomatic period when therapeutic options are limited. This series of cases demonstrates that TE can be utilized for the detection and diagnosis of CPC-the end clinical presentation of noncirrhotic portal hypertension in patients with persistently elevated LFTs but no underlying hepatic disease. Perisinusoidal fibrosis and sinusoidal dilatation were the common histopathological findings and may comprise the index comparator to LSVs. The diagnosis should still be confirmed by biopsy. TE has been shown to detect portal hypertension without significant fibrosis and is a valuable noninvasive investigation in the diagnosis of CPC.

George Panos, MD*

Lavanta Farouk, MD†

Justin Stebbing, MRCP, FRCpath, PhD‡

Paul Holmes, MD*

Sara Valero, MD*

Paul Randell, MD*

Mark Bower, PhD, FRCP*

Brian Gazzard, MD, FRCP*

Mike Anderson, MD§

Mark Nelson, MD*

*HIV/GUM Directorate, Chelsea and Westminster Hospital, St. Stephen's Centre, London, United Kingdom

†Department of Gastroenterology, Imperial College Healthcare NHS Trust, London, United Kingdom

‡Department of Oncology and Surgery, Imperial College Healthcare NHS Trust, London, United Kingdom

§Department of Gastroenterology, Chelsea and Westminster Hospital, London, United Kingdom

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REFERENCES

1. Wanless IR. Micronodular transformation (nodular regenerative hyperplasia) of the liver: a report of 64 cases among 2500 autopsies and a new classification of benign hepatocellular nodules. Hepatology. 1990;11:787-797.

2. Wanless IR, Godwin TA, Allen F, et al. Nodular regenerative hyperplasia of the liver in hematologic disorders: a possible response to obliterative portal venopathy. A morphometric study of nine cases with a hypothesis on the pathogenesis. Medicine (Baltimore). 1980;59:367-379.

3. Saadoun D, Cazals-Hatem D, Denninger MH, et al. Association of idiopathic hepatic sinusoidal dilatation with the immunological features of the antiphospholipid syndrome. Gut. 2004;53:1516-1519.

4. Fraquelli M, Rigamonti C, Casazza G, et al. Reproducibility of transient elastography in the evaluation of liver fibrosis in patients with chronic lives disease. Gut. 2007;56:968-973.

5. Rigamonti C, Donato MF, Fraquelli M, et al. Transient elastography predicts fibrosis progression in patients with recurrent hepatitis C after liver transplantation. Gut. 2008;57:968-973.

6. Carrión JA, Navasa M, Bosch J, et al. Transient elastography for diagnosis of advanced fibrosis and portal hypertension in patients with hepatitis C recurrence after liver transplantation. Liver Transpl. 2006;12:1791-1798.

7. Naber AH, Van Haelst U, Yap SH. Nodular regenerative hyperplasia of the liver: an important cause of portal hypertension in non-cirrhotic patients. J Hepatol. 1991;12:94-99.

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Hasson, H; Merli, M; Galli, L; Gallotta, G; Carbone, A; Messina, E; Bagaglio, S; Morsica, G; Salpietro, S; Castagna, A; Lazzarin, A; Uberti-Foppa, C
Liver International, 33(7): 1113-1120.
10.1111/liv.12159
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