Graves' disease presenting with severe cholestasis

BACKGROUND: Hyperthyroidism has been associated with liver function abnormalities; however, cholestasis as the presenting feature of adolescent Graves' disease has not been previously reported. PATIENT SUMMARY: The patient was a 17-year-old girl who presented with severe cholestasis and was found to have Graves' disease. She also had a positive hepatitis A immunoglobulin M antibody but her clinical course, the liver histopathology, and her mildly elevated transaminases indicated that the acute hepatitis A infection was not dominant at the time of presentation with severe cholestasis. Other causes of cholestasis, including congestive heart failure, autoimmune hepatitis, and viral infection, were excluded. Treatment with methimazole resolved the hyperthyroidism, and the cholestasis improved, as well. CONCLUSION: Severe cholestasis is a rare presenting feature of Graves' disease. With careful monitoring, methimazole can be used to treat the hyperthyroidism in the setting of cholestasis.     

Detection of the cholestatic factor in the liver tissue of patients with acute intrahepatic cholestasis

A novel lymphokine, which we have designated as cholestatic factor (CF), was produced from peripheral blood lymphocytes of patients with drug-induced allergic intrahepatic cholestasis by stimulation with a causative drug in the presence of the liver soluble fraction containing liver-specific lipoprotein (LSP). Marked reductions in bile flow and bile acid excretion were induced in rats by injecting CF through a mesenteric vein. In order to confirm the presence of CF in the liver tissue of patients, we attempted to detect this lymphokine by using the enzyme-labelled antibody method. As a result, CF was found in the liver tissue of eleven out of thirty-eight patients with acute intrahepatic cholestasis including one with hepatitis A type, one with hepatitis B type, two with hepatitis non-A non-B type, five with drug-induced allergic hepatitis, one with alcoholic hepatitis and one with lupoid hepatitis. In contrast, CF was undetectable in the liver tissue of patients without intrahepatic cholestasis. These results may additionally support our assumption that CF plays an important role in the induction of intrahepatic cholestasis in various liver diseases.     

A missense mutation in FIC1 is associated with greenland familial cholestasis

Greenland familial cholestasis is a severe form of intrahepatic cholestasis described among indigenous Inuit families in Greenland. Patients present with jaundice, pruritus, bleeding episodes, and steatorrhea, and die in childhood due to end-stage liver disease. We investigated the possibility that Greenland familial cholestasis is caused by a mutation in FIC1, the gene defective in patients with progressive familial intrahepatic cholestasis type 1 and many cases of benign recurrent intrahepatic cholestasis. Using single-strand conformation polymorphism analysis and sequencing of the FIC1 exons, a missense mutation, 1660 G-->A (D554N), was detected and was shown to segregate with the disease in Inuit patients from Greenland and Canada. Examination of liver specimens from 3 Inuit patients homozygous for this mutation revealed bland canalicular cholestasis and, on transmission electron microscopy, coarsely granular Byler bile, as previously described in patients with progressive familial intrahepatic cholestasis type 1. These data establish Greenland familial cholestasis as a form of progressive familial intrahepatic cholestasis type 1 and further underscore the importance of unimpeded FIC1 activity for normal bile formation.     

Cholestasis secondary to hyperthyroidism made worse by methimazole

A 28-year-old man presented with weight loss, jaundice, and pruritis. This was diagnosed to be secondary to Graves disease and the patient was prescribed methimazole. He returned 2 weeks later with worsening of his jaundice. Further investigation, including liver biopsy, indicated that there was superimposed methimazole-induced cholestasis. Discontinuation of methimazole and treatment of hyperthyroidism with lithium followed by radioactive iodine therapy resulted in resolution of his symptoms. This case highlights the fact that worsening cholestasis after therapy for Graves disease should raise the possibility of thionamide-induced exaggeration of liver cholestasis.     

Bimodal peaks of liver stiffness in a case of drug‐induced liver injury

A 69‐year‐old male complained of general fatigue and presented with elevation of liver enzymes without any cause of liver injury. We diagnosed him with hepatocellular drug‐induced liver injury (DILI). Liver stiffness, which was evaluated according to the shear wave velocity (SWV) using virtual touch tissue quantification, was serially observed during hospitalization. A fast SWV was noted on the date of admission, indicating a “hard” degree of liver stiffness. The SWV gradually decreased until the 20th hospital day. However, the patient's liver enzymes again became elevated on the 20th hospital day, and the SWV simultaneously increased in association with a rise in the total bilirubin level. The laboratory data for the second peak of the SWV indicated mixed‐type DILI; therefore, the patient's pathological state transitioned from the hepatocellular type to the mixed type. A liver biopsy performed before discharge revealed a state of recovery from acute inflammation without fibrotic changes. We conclude that the second peak of the SWV may be affected by the presence of intrahepatic cholestasis. We herein report the occurrence of bimodal peaks of liver stiffness in a patient with DILI. In such cases, each peak of liver stiffness may be the result of a different pathological mechanism, namely acute inflammation versus acute intrahepatic cholestasis. Although the detailed mechanisms underlying the development of liver stiffness due to intrahepatic cholestasis remain unclear, this case presented a limitation of virtual touch tissue quantification for evaluation of liver stiffness as fibrosis marker in the liver with intrahepatic cholestasis.     

CHOLESTASIS IN ACUTE ALCOHOLIC LIVER DISEASE

10 of a series of 108 patients with alcoholic liver disease presented with cholestasis associated with non-cirrhotic alcoholic liver disease and without evidence of extrahepatic biliary obstruction. In 7 patients liver histology and the associated conditions presenting as cholestasis were heterogeneous. However, in 3 patients who had been drinking excessively before cholestatic jaundice developed, cholestasis was a major feature of liver histology. The term acute alcoholic cholestasis is suggested for this apparently distinct syndrome of cholestatic jaundice in the absence of hepatitis.     

Study of adiponectin in chronic liver disease and cholestasis

Purpose

Adiponectin is an adipocytokine suggested to have a hepatoprotective effect. To date, little information is available in the literature regarding changes in serum adiponectin levels in cirrhosis and cholestasis and the associated metabolic disturbances. In order to elucidate the role of adiponectin in chronic liver disease our aim was to determine serum adiponectin in patients with different grades of cirrhosis and cholestasis and to correlate it with markers of liver injury, inflammation and cholestasis. We also aimed to correlate adiponectin with markers of metabolic syndrome such as body mass index and insulin resistance.

Methods

Forty patients with cirrhosis; 30 patients with cirrhosis and cholestasis; and 20 matched controls were studied. They were subjected to clinical assessment, laboratory investigations: serum bilirubin, ALT, AST, alkaline phosphatase, GGT, albumin, C-reactive protein, prothrombin activity, fasting blood sugar, insulin. HOMA index was calculated. Abdominal ultrasonography and upper GI endoscopy were performed.

Results

Adiponectin was elevated in patients with cirrhosis and cirrhosis/cholestasis and was significantly higher in Child A and B. Adiponectin showed correlation with liver cell injury, marker of inflammation, synthetic liver function and markers of cholestasis. Adiponectin did not correlate with complications of cirrhosis as ascites and esophageal varices nor did it correlate with BMI or HOMA.

Conclusions

Adiponectin is elevated in cirrhosis and shows correlation with degree of hepatocellular injury and cholestasis. Finally, adiponectin levels in cirrhosis do not correlate with parameters of body composition or metabolism but exclusively with reduced liver function.     

肝硬化患者并发感染相关性胆汁淤积症54例临床特点及转归

目的加强对肝硬化患者并发感染相关性胆汁淤积症的认识,分析肝硬化患者并发感染相关性胆汁淤积症的临床特点、危险因素及转归。方法回顾性分析肝硬化患者并发感染相关性胆汁淤积症的临床资料,分析其临床特征及其预后,比较54例肝硬化患者并发感染相关性胆汁淤积症与同期住院的发生感染但未出现胆汁淤积症（对照组）126例肝硬化患者在年龄、性别、Child-Pugh分级、早期及时经验性抗菌药物应用的差异。结果 54例肝硬化患者并发感染相关性胆汁淤积症的感染部位：腹腔感染（自发性细菌性腹膜炎,SBP）20例、尿路感染18例、胆道感染6例、肠道感染4例、肺部感染4例、部位不明确2例,根据Child-Pugh分级约有55.56%的患者为Child C级。两组比较,年龄、Child-Pugh分级、早期及时经验性应用抗菌药物等,差异均有统计学意义（P〈0.05）;观察组中病死率15.00%,高于对照组的4.36%,差异有统计学意义（P〈0.05）。结论肝硬化患者并发感染相关性胆汁淤积症对预后有不良影响,尤其合并有肝肾综合征者病死率较高,应高度重视临床及实验诊断,针对其临床特征实施相应措施。     

Clinical features of biochemical cholestasis in patients with recurrent hepatitis C after living‐donor liver transplantation

Summary. Recurrent hepatitis C after liver transplantation (HepC‐LT) progresses faster than hepatitis C in non‐transplant settings. Cholestasis has been suggested to be one characteristic of HepC‐LT related to the rapid progression. We investigated the clinical features of biochemical cholestasis, which we defined as high serum concentrations of alkaline phosphatase and γ‐glutamyl transpeptidase, in patients with recurrent hepatitis C after living‐donor liver transplantation. Eighty patients were diagnosed with post‐transplant recurrent hepatitis C after exclusion of other aetiologies of cholestasis by liver biopsy and imaging. The clinical features of biochemical cholestasis in the patients with HepC‐LT, including histological changes, the efficacy of interferon therapy and helper T‐cell (Th) subsets in the peripheral blood, were analysed. Fifty‐five of the 80 patients with HepC‐LT (69%) had evidence of biochemical cholestasis. Progression of liver fibrosis to stage F3 or F4 was significantly accelerated in patients with biochemical cholestasis compared with patients without cholestasis. The biochemical cholestasis in patients with HepC‐LT improved after interferon therapy in 22 of 39 patients (56%) who showed a virological response to the therapy, suggesting that hepatitis C virus (HCV) caused the biochemical cholestasis in these patients. Patients with biochemical cholestasis who had a biochemical response to interferon therapy showed an increased Th1 responses in peripheral blood. In conclusion, biochemical cholestasis is the characteristic feature of HepC‐LT and is related to progression of liver fibrosis. An increased Th1 response is associated with cholestasis caused by HCV after liver transplantation.     

Intrahepatic cholestasis: clinical and nosological classification. Critical survey of personal experience

We reviewed 20 patients (16 females and 4 males) with intrahepatic cholestasis and recognised the following miscellaneous disorders: 12 primary biliary cirrhosis (PBC), 3 primary sclerosing cholangitis (PSC), 1 immune cholangiopathy (IC), 3 liver sarcoidosis and 1 cholestasis with Horton's arteritis. The aim of the study was to identify potentially differetiating clinical and biochemical findings in intrahepatic cholestasis. Sixty females were affected with changes reflecting a cholestatic pattern including an elevated alkaline phosphatasis and gammaglutamyltransferase level. Pruritus was found in 50 percent of PBC patients; fever addressed often, in liver sarcoidosis and Horton's arteritis. A striking increase of unesterified cholesterol was a common feature of PBC. An elevated polyclonal serum IgM in PBC such as in PSC. A circulating IgM antimitochondrial antibody and antinuclear antibodies were found in 90 percent of PBC patients; isolated antinuclear antibodies were detected in immune colangiopathy patients (IC). Liver biopsy was necessary to establish the diagnosis of intrahepatic cholestasis. Overlapping histopathologic features made diagnosis hard in cholestatic disorders, all but in liver sarcoidosis. Treatment with UDCA or TUDCA+/-colchicin, reduced cholestatic enzymes in 85 percent of PBC cohort, while it was unsuccessful in PSC-group. Steroid treatment was successful in sarcoidosis, Horton's arteritis and immune colangiopathy. Cy A did not improve clinical and biochemical features in PBC.     

Hyperbilirubinemia and cholestatic liver injury in hepatitis C-infected liver transplant recipients

OBJECTIVE: A cholestatic pattern of liver injury has been observed in liver transplant recipients with rapidly progressive hepatitis C. We assessed the frequency and causes of cholestasis in hepatitis C-infected liver transplant patients, and evaluated the clinical and pathological course of those with cholestatic hepatitis C. METHODS: Sixty-nine sequential liver transplant recipients who had detectable hepatitis C viremia were studied retrospectively. Records and diagnostic tests were examined from patients who developed hyperbilirubinemia. RESULTS: Hyperbilirubinemia occurred in 33 of 69 (48%) hepatitis C-infected liver transplant patients. A thorough evaluation including review of clinical and laboratory data, ultrasound with Doppler, cholangiogram, and liver biopsy identified causes of hyperbilirubinemia other than hepatitis C in 26 of 33 patients. Seven patients developed cholestatic hepatitis C characterized by histological features of recurrent hepatitis C and cholestatic liver injury with ballooning of centrilobular hepatocytes, bile ductular proliferation, and canalicular cholestasis, in the absence of other causes of cholestasis. Five progressed rapidly to bridging fibrosis and two died of complications related to liver failure. Four patients with cholestatic hepatitis C showed extended survival after the onset of hyperbilirubinemia. CONCLUSIONS: 1) Hepatitis C is a relatively infrequent cause of cholestasis in liver transplant recipients. 2) The diagnosis of cholestatic hepatitis C requires a multimodality approach to exclude other causes of cholestasis. 3) Cholestatic hepatitis C ranges in severity and is not always associated with rapid development of graft failure, although significant histological abnormalities are frequent.     

Vitamin A-induced cholestatic hepatitis: a case report

We report a case of intrahepatic cholestasis due to chronic vitamin A supplementation. A 70-year-old woman was admitted to the hospital for jaundice and reduced nutritional and general status with a 2-month history of increasing cholestasis. Some years previously she had suffered from breast and ovarian cancer with subsequent surgery and chemotherapy. Chemotherapy was terminated one month before elevated serum transaminase activities and cholestatic serum markers were noted. Following the chemotherapy, supportive care included weekly vitamin A injections (100,000 IU per injection). Liver biopsy showed an acute toxic liver injury with focal parenchymal necrosis, sinusoidal lesions, inflammatory infiltrate (round cells, macrophages), and activation and proliferation of stellate cells. The hepatic vitamin A concentration was found to be significantly elevated. There were no signs of intrahepatic metastasis or liver cirrhosis. Treatment with ursodeoxycholic acid rapidly improved the cholestasis and led to a total recovery after three weeks.     

Studies on drug-induced allergic intrahepatic cholestasis--hepatic cholestasis induced in dogs by lymphocyte culture supernatant.

When peripheral lymphocytes from patients with drug-induced allergic intrahepatic cholestasis were stimulated with a specific drug in vitro in the presence of a liver microsome fraction or soluble liver specific antigen fraction, lympholine production was seen in many cases. By the injection of culture supernatant of stimulated lymphocytes into the mesentery vein of dogs, cholestasis was induced in the liver, chiefly in the central zones of lobules. However, no cholestasis could be observed in dogs administered the supernatants of lymphocyte cultures prepared from normal individuals in the presence of drugs. Moreover, only slight swelling of the hepatocytes was observed in the liver when normal lymphocytes were stimulated with PHA-P and culture supernatant was injected into the mesentery vein of dogs. These results suggest that sensitized lymphocytes may produce a factor (or factors) by stimulation with a specific drug-carrier and this factor (or factors) causes cholestasis in the liver.     

Indomethacin-associated cholestasis

A patient with no prior history of liver disease developed mild cholestasis, with a moderate elevation of the serum alkaline phosphatase level, several days after instituting indomethacin therapy. The cholestasis resolved soon after the medication was discontinued. An extensive workup, including liver biopsy, revealed no alternative cause. Despite extensive use, indomethacin therapy has been associated with hepatic injury in only nine previously reported cases, as near as we can tell.     

Subacute cholestatic hepatitis likely related to the use of senna for chronic constipation

We report a case of senna-induced cholestatic hepatitis which was not diagnosed at presentation. A 77 year old male was referred with abdominal pain, jaundice and elevated transaminase levels. A diagnosis of extrahepatic cholestasis was first suspected, due to the observation of a duodenal diverticulum and dilated proximal choledocus. However, the sphincterotomy did not improve cholestasis. At further evaluation, HBsAg was positive but serological work up was compatible with a healthy-carrier status. Further interrogation of the patient revealed a history of chronic senna intake to treat a chronic constipation. Liver biopsy showed bridging hepatocellular necrosis as well as canalicular cholestasis. Drug withdrawal resulted in a slow and progressive reduction in bilirubin levels and liver enzymes. In this case senna was likely the cause of a subacute cholestatic hepatitis exemplifying again the potential role of herbal related liver injury.     

Neonatal cholestasis and hepatosplenomegaly caused by congenital dyserythropoietic anemia type 1: A case report

BACKGROUND Congenital dyserythropoietic anemia type 1(CDA1) is an autosomal recessive disorder of ineffective erythropoiesis, resulting in increased iron storage. CDA1 is usually diagnosed in children and adolescents but can rarely present in the neonatal period with severe anemia at birth. There are no prior reports of neonatal liver histologic findings of CDA1. We report a case of CDA1 in a newborn presenting with severe anemia, cholestasis and liver failure, where liver biopsy helped confirm the diagnosis.CASE SUMMARY A term infant, born via emergency Cesarean section, presented with cholestasis,hepatosplenomegaly, multiorgan failure and severe anemia at birth. A prior pregnancy was significant for fetal demise at 35 wk without autopsy or known etiology for the fetal demise. Parents are both healthy and there is no history of consanguinity. On further evaluation, the patient was found to have severe ferritin elevation and pulmonary hypertension. An extensive infectious and metabolic work-up was negative. Salivary gland biopsy was negative for iron deposition. At 2 wk of age, a liver biopsy showed findings consistent with CDA1.A genome rapid sequencing panel revealed novel variants in the CDAN1 gene.The patient's liver dysfunction, cholestasis and organomegaly resolved, however she remains transfusion-dependent.CONCLUSION We report liver pathology findings of CDA1 with a novel genetic mutation for the first time in a newborn.     

Successful liver transplantation for acute sickle cell intrahepatic cholestasis: A case report and review of the literature

BACKGROUND Sickle cell hepatopathy(SCH) is an inclusive term referring to any liver dysfunction among patients with sickle cell disease. Acute sickle cell intrahepatic cholestasis is one of the rarest and most fatal presentations of SCH. We present the 23 rd reported case of liver transplantation(LT) for SCH; a rare case of acute sickle cell intrahepatic cholestasis managed with LT from a hepatitis C virus(HCV) nucleic acid amplification test positive donor.CASE SUMMARY A 29-year-old male with a past medical history of sickle cell disease presented with vaso-occlusive pain crisis. On examination, he had jaundice and a soft, nontender abdomen. Initially he was alert and fully oriented; within 24 h he developed new-onset confusion. Laboratory evaluation was notable for hyperbilirubinemia, leukocytosis, anemia, thrombocytopenia, acute kidney injury and elevated international normalized ratio(INR). Imaging by ultrasound and computed tomography scan suggested a cirrhotic liver morphology with no evidence of biliary ductal dilatation. The patient was diagnosed with acute sickle cell intrahepatic cholestasis after excluding competing etiologies of acute liver injury. He underwent LT from an HCV nucleic acid amplification test positive donor 9 d after initial presentation. The liver explant was notable for widespread sinusoidal dilatation with innumerable clusters of sickled red blood cells and cholestasis. On postoperative day 3, HCV RNA was detectable in the patient's peripheral blood and anti-HCV therapy with glecaprevir/pibrentasvir was initiated on postoperative day 23. He subsequently achieved sustained virologic response after completing 3 mo of therapy and has been followed clinically for 12 mo post-transplant.CONCLUSION This case highlights the utility of LT as a viable treatment option for acute sickle cell intrahepatic cholestasis.     

β-hexosaminidase in bile and plasma from patients with cholestasis

Abstract: β-Hexosaminidase (Hex) activity was determined in bile from 18 patients with cholestasis, six patients without cholestasis and in ten normal liver biopsies. The difference in the mean activities in bile from patients with and without cholestasis was not significant. Only about 0.5 promille of total liver Hex activity was lost per day via the bile flow. Gel chromatography showed that enzyme forms present in bile had higher molecular weights than the forms present in liver tissue, indicating that the biliary enzyme was not routed through the lysosomes before release into the bile. In 32 patients with cholestasis, plasma Hex was increased compared to controls, and correlated to bilirubin. The activity was significantly higher in patients with severe cholestasis than in patients with less severe forms of cholestasis, but no significant difference in Hex activity was observed between patients with benign or malignant biliary obstruction. No significant difference was noted between patients with cholestasis for less than 1 week compared to those whose illness had lasted more than 1.5 weeks. The impact of biliary obstruction on plasma Hex is further illustrated by the observation that decompression lowered plasma Hex as well as bilirubin and alkaline phosphatase.     

Differential alterations of cytochrome P450 proteins in livers from patients with severe chronic liver disease

To determine whether cytochrome P450 proteins were differentially altered in severe chronic liver diseases, we examined 50 livers removed at liver transplantation from patients with end-stage cirrhosis, including 18 with and 32 without cholestasis, and compared the results with 21 histologically normal livers. NADPH-cytochrome c reductase activities were unaltered in microsomes from cirrhotic livers. Total cytochrome P450 content was significantly reduced. The catalytic activities of four xenobiotic-metabolizing P450s and the level of the corresponding proteins were differentially altered. Thus, P450 3A-supported testosterone 6β-hydroxylase activity and 3A protein appeared to be reduced, but only in the subgroup without cholestasis was this change significant. In contrast, 2E1 and the related N,N-dimethylnitrosamine N-demethylase activity were clearly reduced in livers from patients with cholestatic forms of cirrhosis but appeared not to be changed in other cirrhotic livers. Similarly, P450 2C protein was reduced only in patients with severe chronic cholestasis. Finally, P450 1A2 and 1A2-supported ethoxyresorufin O-deethylase activity were significantly reduced in hepatic microsomes from patients with both types of advanced liver disease. In summary, these data demonstrate that cytochrome P450 proteins are selectively altered in severe chronic liver disease, some being profoundly decreased, others less so or not at all. Our results also suggest that there may be different patterns of altered hepatic P450 expression according to the presence or absence of cholestasis in patients with cirrhosis severe enough to require transplantation.