Focus
Authors: Daniel Shouval
Journal: Journal of Hepatology (2009)

Thrombocytopenia is a common phenomenon in chronic HCV infection. It has previously been linked to hepatic fibrosis, portal hypertension, sequestration of platelets associated with splenomegaly and the detection of HCV-RNA in platelets of infected patients. Previous reports by Lerat et al. (JCI 1996;97:845), de Almeira et al. (Ann Hematology 2004;83:434 and Hepatogastroenterology 2007;54:964) and others revealed presence of HCV-RNA with higher frequency in thrombocytopenic patients as compared to non-thrombocytopenic individuals. This suggests that HCV is involved directly or indirectly in the process of thrombocytopenia. In this issue of the Journal of Hepatology, Chai-Yen Dai et al. confirmed an association between low-platelet count and HCV viremia in a community-based study performed in Taiwan with 11,232 residents of whom 703 (6.2%) were anti-HCV positive. The main finding of their study is a statistically-significant correlation between low-platelet count (<150,000 mm3) and qualitative detection of HCV-RNA and elevated ALT values, after adjustment for fibrosis using a FibrotTest. This significant correlation was confirmed by uni- and multi-variate analysis and by using a control group of patients with biopsy proven CLD and chronic HCV. The authors suggest that their results support the hypothesis that platelets may be affected directly by HCV. Indeed this controlled study provides further indirect support for the assumption that HCV-RNA may directly (or indirectly) suppress formation or maturation of platelets. Yet, this putative effect still remains a hypothesis until further information is obtained regarding the molecular mechanism of this phenomenon. The strength of this observation relies on the large community-based evaluation and the methodology used for assessment. However, as noted by the authors, the study has a number of limitations since it lacks controls for a number of factors known to be associated with thrombocytopenia in HCV including: spleen size, portal hypertension and autoimmune-thrombocytopenia. Nonetheless, this report strengthens the observation that there seems to be an independent effect on HCV viremia on platelet count. Further studies will be required to decipher a potential molecular mechanism. Hepatic Elastography-Fibroscan (FS) and Fibrotest have captured the attention of hepatologists world wide as a non-invasive means to assess fibrosis and inflammatory activity, instead of the more invasive liver biopsy. In the ongoing process of gaining experience with these procedures, it has become clear that despite their reported specificity and sensitivity, these modalities are not always useful in some defined hepatic conditions. Case reports on false-positive results mimicking advanced cirrhosis have been published for FS in obese patients with ascites, viral hepatitis, cholestasis, and congestive heart failure. In this issue of the Journal, Millonig and coworkers have designed an animal model system of hepatic congestion in pigs through clamping of the inferior and superior vena cava and then tested the performance of FS under these conditions. They also used their animal model to study the effect of portal vein and hepatic artery clamping on liver stiffness. The investigators have clearly shown that a progressive increase in intravascular pressure in the vena cava leads to a linear and reversible increase in liver stiffness as measured by transient elastography; thus, mimicking stiffness measurements in cirrhosis of the liver. They then confirmed their observation in the experimental model in 8/10 patients with well-defined congestive heart failure. In these patients, results of the FS were compatible with the diagnosis of cirrhosis. Conventional treatment of the underlying congestion (i.e. diuretics) leads to a decrease in liver stiffness as measured by FS by up to 50%. The methodology used in the experimental animal system as well as in humans with congestive heart failure is sound and the result will be of value to the clinician who desires to assess the degree of hepatic fibrosis prior to therapeutic interventions (i.e. anti-viral treatment in hepatitis C). Thus, this elegant paper uses an experimental model to prove the concept that congestive heart failure may lead to increased liver stiffness mimicking cirrhosis of the liver, a situation which is reversible by vascular declamping or pharmacological decongestion. The obvious conclusion of this study is that prior to utilization of the fibroscan, clinicians must verify that their patients do not have congestive heart failure and if so treat the condition prior to performing the liver stiffness measurements. In this issue of the journal, Ben-Ari and coworkers describe a case of hyperammonemic encephalopathy in a 47 year-old male who started an Atkins high protein, low carbohydrate, and low fat diet a few days prior to clinical presentation. The patient presented with lethargy, somnolence, seizures, and encephalopathy with radiological evidence for brain edema. Serum ammonia levels reached 541 μg/deciliter while serum glutamine levels were increased in the presence of low serum citrullin and secretion of orotic acid and uracil in urine. ALT and AST were mildly elevated with normal albumin and prothrombin time values. These findings led to the tentative diagnosis of the X-linked OTC deficiency after ruling out systemic neurological and hepatic disorders. The diagnosis of OTC deficiency was confirmed by genetic analysis at a later stage. A novel hemizygous missense mutation in exon 5 was identified, which was also present in other family members. The patient’s condition improved rapidly after treatment by artificial respiration, hemodialysis low-protein diet, administration l-arginine and sodium phenylbutirate and hyperalimentation with glucose and intralipid. The urea cycle OTC deficiency is a relatively rare metabolic disorder, reported mainly in neonates and young babies and rarely in male adults. The outcome of this disorder is often fatal in babies. In adults, it may remain asymptomatic for long periods, even for a lifetime, but occasionally can present after ingestion of a high-protein diet, pregnancy, or intake of certain drugs including corticosteroids. Hepatologists and neurologists have rarely a chance to encounter such patients. However, in recent years, the weight reducing Atkins diet is becoming very popular in the Western hemisphere and especially in the United States. It is reported that one of every eleven US citizens has tried the Atkins diets in the early 2000s. In view of the fact that OTC deficiency is prevalent in 1/8000–14,000 births, it is rather surprising that until now, this metabolic disorder was not diagnosed more frequently although concern regarding the unmasking of this entity by the Atkins diet has been raised for some time. The question remains open whether this is a very rare anecdotal case report of OTC deficiency unmasked by the Atkins diet (and possibly worsened by short-term anti-convulsant treatment with Valporate known to induce hyperammonemia) or indeed there are more patients out there who consume the Atkins diet, who do not develop the full clinical spectrum of the disease and remain undiagnosed. Special attention may be justified in obese patients with non-alcoholic fatty liver disease and preserved liver functions who embark on an Atkins diet and develop neurological symptoms. Thus, the purpose of presenting this case report is to alert clinicians to this rare condition.