Glycogenic hepatopathy:A narrative review

Glycogenic hepatopathy(GH) is a rare complication of the poorly controlled diabetes mellitus characterized by the transient liver dysfunction with elevated liver enzymes and associated hepatomegaly caused by the reversible accumulation of excess glycogen in the hepatocytes. It is predominantly seen in patients with longstanding type 1 diabetes mellitus and rarely reported in association with type 2 diabetes mellitus. Although it was first observed in the pediatric population, since then, it has been reported in adolescents and adults with or without ketoacidosis. The association of GH with hyperglycemia in diabetes has not been well established. One of the essential elements in the pathophysiology of development of GH is the wide fluctuation in both glucose and insulin levels. GH and non-alcoholic fatty liver disease(NAFLD) are clinically indistinguishable, and latter is more prevalent in diabetic patients and can progress to advanced liver disease and cirrhosis. Gradient dual-echo MRI can distinguish GH from NAFLD; however, GH can reliably be diagnosed only by liver biopsy. Adequate glycemic control can result in complete remission of clinical, laboratory and histological abnormalities. There has been a recent report of varying degree of liver fibrosis identified in patients with GH. Future studies are required to understand the biochemical defects underlying GH, noninvasive, rapid diagnostic tests for GH, and to assess the consequence of the fibrosis identified as severe fibrosis may progress to cirrhosis. Awareness of this entity in the medical community including specialists is low. Here we briefly reviewed the English literature on pathogenesis involved, recent progress in the evaluation, differential diagnosis, and management.

Glycogenic hepatopathy

Background: Glycogenic hepatopathy(GH) is a disorder associated with uncontrolled diabetes mellitus,most commonly type 1, expressed as right upper quadrant abdominal pain, hepatomegaly and increased liver enzymes. The diagnosis may be difficult, because laboratory and imaging tests are not pathognomonic. Although GH may be suggested based on clinical presentation and imaging studies, the gold standard for diagnosis is a liver biopsy, showing a significant accumulation of glycogen within the hepatocytes. GH may be diagnosed also after elevated liver enzymes in routine blood tests. GH usually regresses after tight glycemic control. Progression to end-stage liver disease has never been reported. This review aims to increase the awareness to this disease, to suggest a pathway for investigation that may reduce the use of unnecessary tests, especially invasive ones.Data sources: A Pub Med database search(up to July 1, 2017) was done with the words "glycogenic hepatopathy", "hepatic glycogenosis", "liver glycogenosis" and "diabetes mellitus-associated glycogen storage hepatopathy". Articles in which diabetes mellitus-associated liver glycogen accumulation was described were included in this review.Results: A total of 47 articles were found, describing 126 patients with GH. Hepatocellular disturbance was more profound than cholestatic disturbance. No synthetic failure was reported.Conclusions: GH may be diagnosed conservatively, based on corroborating medical history, physical examination, laboratory tests, imaging studies and response to treatment, even without liver biopsy. In case of doubt about the diagnosis or lack of clinical response to treatment, a liver biopsy may be considered.There is no role for noninvasive tests like fibroscan or fibrotest for the diagnosis of GH or for differentiation of this situation from nonalcoholic fatty liver disease.

Mitochondrial hepatopathy: Anticipated difficulties in management of fatty acid oxidation defects and urea cycle defects

Fatty acid oxidation defects(FAOD)and urea cycle defects(UCD)are among the most common metabolic liver diseases.Management of these disorders is dotted with challenges as the strategies differ based on the type and severity of the defect.In those with FAOD the cornerstone of management is avoiding hypoglycemia which in turn prevents the triggering of fatty acid oxidation.In this review,we discuss the role of carnitine supplementation,dietary interventions,newer therapies like triheptanoin,long-term treatment and approach to positive newborn screening.In UCD the general goal is to avoid excessive protein intake and indigenous protein breakdown.However,one size does not fit all and striking the right balance between avoiding hyperammonemia and preventing deficiencies of essential nutrients is a formidable task.Practical issues during the acute presentation including differential diagnosis of hyperammonemia,dietary dilemmas,the role of liver transplantation,management of the asymptomatic individual and monitoring are described in detail.A multi-disciplinary team consisting of hepatologists,metabolic specialists and dieticians is required for optimum management and improvement in quality of life for these patients.

Mitochondrial hepatopathy: Respiratory chain disorders- ‘breathing in and out of the liver’

Mitochondria,the powerhouse of a cell,are closely linked to the pathophysiology of various common as well as not so uncommon disorders of the liver and beyond.Evolution supports a prokaryotic descent,and,unsurprisingly,the organelle is worthy of being labeled an organism in itself.Since highly metabolically active organs require a continuous feed of energy,any dysfunction in the structure and function of mitochondria can have variable impact,with the worse end of the spectrum producing catastrophic consequences with a multisystem predisposition.Though categorized a hepatopathy,mitochondrial respiratory chain defects are not limited to the liver in time and space.The liver involvement is also variable in clinical presentation as well as in age of onset,from acute liver failure,cholestasis,or chronic liver disease.Other organs like eye,muscle,central and peripheral nervous system,gastrointestinal tract,hematological,endocrine,and renal systems are also variably involved.Diagnosis hinges on recognition of subtle clinical clues,screening metabolic investigations,evaluation of the extrahepatic involvement,and role of genetics and tissue diagnosis.Treatment is aimed at both circumventing the acute metabolic crisis and long-term management including nutritional rehabilitation.This review lists and discusses the burden of mitochondrial respiratory chain defects,including various settings when to suspect,their evolution with time,including certain specific disorders,their tiered evaluation with diagnostic algorithms,management dilemmas,role of liver transplantation,and the future research tools.

Etiology Based Sickle Cell Disease Hepatopathy

Sickle cell disease is an autosomal recessive disorder. The vas-occlusive crises lead to microinfarcts in the microvasculature in all organs, including the liver causing acute and chronic vascular complications in the form of ischemia, sequestration, and thrombosis, it also causes acute on top of chronic hepatic manifestations. Lifelong hemolytic anemia leads to precipitations of bile salts, bile pigments in intrahepatic, and extrahepatic bile ducts, which cause an important part of liver problems in sickle cell disease. Many other etiological factors could cause sickle cell disease hepatopathy. Liver problems in such patients could be fatal complications. Dealing with these complications based on the etiological factors provides a more accurate diagnosis for the overlapping liver manifestations in sickle cell disease, which means better treatment;it also simplifies this complicated medical issue. Sickle cell disease patients require periodic biochemistry and imaging studies to detect and treat hepatic complications as soon as possible.

Sickle Hepatopathy and Complex Jaundice in a Primigravida with Hepatitis B Virus Infection: Case Report

Background Aim: This article aimed to sensitize the healthcare providers who care for patients with sickle cell disease (SCD) during pregnancy, to the multiple causes of jaundice in sickle hepatopathy, and sift the maze in establishing the dominant cause. Case Presentation: This is a case of a 28-yr-old Gravida 1 Para 0 + 0 health worker, with sickle cell anaemia and background history of peptic ulcer disease, total right hip replacement and previous multiple blood transfusions due to haemolytic crisis. She presented with upper abdominal pain and progressively deepening jaundice. There was minimal relief of the abdominal pain with anti-ulcer medications. She had tender hepatomegaly, positive Murphy’s sign and deranged liver function parameters. She was also positive for viral hepatitis B markers. A remarkable finding on abdominal ultrasonography was that of a gallbladder with normal wall thickness and multiple stones. She was managed conservatively on intravenous fluids, antibiotics and Livolin forte (Phosphatidylcholine) with improved liver function parameters within a week. Conclusion: Since sickle cell hepatopathy is multifactorial, the importance of unravelling the dominant cause of jaundice or liver dysfunction in these patients and the need for immediate intervention are necessary for effective and targeted care, hence this case report. Our patient had background chronic hepatitis B with a superadded acute cholecystitis with non-obstructing gallstones, and possible subsequent bacterial hepatitis, which responded to antibiotics. The most likely dominant cause of jaundice was chronic hepatitis B that was precipitated by acute cholecystitis.

Gastrointestinal complications of diabetes mellitus

Diabetes mellitus affects virtually every organ system in the body and the degree of organ involvement depends on the duration and severity of the disease,and other co-morbidities.Gastrointestinal(GI) involvement can present with esophageal dysmotility,gastro-esophageal reflux disease(GERD),gastroparesis,enteropathy,non alcoholic fatty liver disease(NAFLD) and glycogenic hepatopathy.Severity of GERD is inversely related to glycemic control and management is with prokinetics and proton pump inhibitors.Diabetic gastroparesis manifests as early satiety,bloating,vomiting,abdominal pain and erratic glycemic control.Gastric emptying scintigraphy is considered the gold standard test for diagnosis.Management includes dietary modifications,maintaining euglycemia,prokinetics,endoscopic and surgical treatments.Diabetic enteropathy is also common and management involves glycemic control and symptomatic measures.NAFLD is considered a hepatic manifestation of metabolic syndrome and treatment ismainly lifestyle measures,with diabetes and dyslipidemia management when coexistent.Glycogenic hepatopathy is a manifestation of poorly controlled type 1 diabetes and is managed by prompt insulin treatment.Though GI complications of diabetes are relatively common,awareness about its manifestations and treatment options are low among physicians.Optimal management of GI complications is important for appropriate metabolic control of diabetes and improvement in quality of life of the patient.This review is an update on the GI complications of diabetes,their pathophysiology,diagnostic evaluation and management.

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 23rd 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.

Extreme hyperbilirubinemia: An indicator of morbidity and mortality in sickle cell disease

BACKGROUND Sickle cell disease(SCD) is a disorder that results in increased hospitalizations and higher mortality. Advances in management have resulted in increases in life expectancy and led to increasing awareness of sickle cell hepatopathy(SCH).However, its impact in patients on the natural history and outcomes of SCD is not known. Our study aims to describe the prevalence of extreme hyperbilirubinemia(EH), one form of SCH, its effect on morbidity and mortality,and correlations between sickle cell genotype and SCH type. We hypothesize that EH is associated with higher morbidity and mortality.AIM To investigate the effects of EH on morbidity and mortality among patients with SCD.METHODS This retrospective cohort study was performed using a database of patients with SCD treated at Grady Memorial Hospital between May 2004 and January 2017.Patients with EH(defined as total bilirubin above 13.0 mg/dL) were identified. A control group was identified from the same database with patients with total serum bilirubin ≤ 5.0 mg/dL. Electronic medical records were used to extract demographic information, laboratory values, radiology results, current medications, need for transfusions and mortality data. Two samples T-test, chi-squared test and Fisher's exact test were then used to compare the parameters between the two groups.RESULTS Out of the database, fifty-seven charts were found of patients with bilirubin > 13 mg/dL. Prevalence of severe SCH as defined by EH was 4.8%(57/1172). There were no demographic differences between patients with and without EH.Significant genotypic differences existed between the two groups, with hemoglobin SS SCD being much higher in the EH group(P < 0.001). Patients with severe EH had a significant elevations in alanine aminotransferase(157.0 ± 266.2 IU/L vs 19.8 ± 21.3 IU/L, P < 0.001), aspartate aminotransferase(256.5 ± 485.9 U/L vs 28.2 ± 14.7 U/L, P < 0.001) and alkaline phosphatase(218.0 ± 176.2 IU/L vs 85.9 ± 68.4 IU/L, P < 0.001). Patients with EH had significantly higher degree of end organ failure measured with quick Sequential Organ Failure Assessment scores(0.42 ± 0.68 vs 0.01 ± 0.12, P < 0.001), increased need for blood products(63% vs 5%, P < 0.001), and exchange transfusions(10.5% vs 1.3%, P = 0.022).CONCLUSION Among patients with SCD, elevated levels of total bilirubin are rare, but indicative of elevated morbidity, mortality, and need for blood transfusions.Large differences in sickle cell genotype also exist, but the significance of this is unknown.

Protective Effects of Sepia Ink Melanin on Hepatic Tissue in Streptozotocin-Induced Diabetic Mice

Diabetes mellitus(DM)has emerged as a serious public health concern,due to the high morbidity and mortality resulted from its complications,such as diabetic nephropathy,diabetic cardiovascular complication,and diabetic neuropathy,etc.In this study,we investigated the beneficial effects of sepia ink melanin(SIM)on hyperglycaemia and the restoration of diabetic symptoms in streptozotocin(STZ)-induced diabetic model mice.At first,the normal experimental mice were performed with intraperitoneal injection of STZ(40 mg(kg BW)^(−1))(BW,body weight)to attain diabetes and then were treated with different concentrations of SIM(120,240 and 480 mg(kg BW)^(−1))for four weeks.After treatment,significant decrease in gluconeogenesis were determined,accompanied by a notable increase in both glycolysis and oxidative enzyme activities in SIM-treated groups,such as liver marker enzymes in the serum and key antioxidant enzymes in liver.qPCR results revealed the transcriptional alterations in SIM-treated groups.SIM exposure increased the expression levels of several genes related to insulin transduction and PI3K/Akt pathway,including PI3K,Akt,Irs-2,and InsR.Meanwhile,expression levels of Dicarbonyl/l-xylulose reductase(Dcxr)and UDP-glucose dehydrogenase(Ugdh),which are in-volved in pentose-glucuronate interconversion pathway,were also elevated in SIM-treated groups.Furthermore,histological observation results indicated that nuclear deformation and organelle dissolution were improved,thus could enhance the liver function.These results demonstrated that SIM can be effective in ameliorating diabetic symptoms and improving disease management for diabetic patients.

Congestive heart failure masquerading as acute abdomen:A case report

Rationale:As an uncommon manifestation of congestive heart failure,congestive hepatopathy requires an early diagnosis in order to render appropriate care.Misdiagnosis as intraabdominal sepsis may lead to erroneous initial intervention,such as fluid boluses,that can potentially tip an already sick patient with poor reserves over into an extreme state.Patient’s Concern:A 65-year-old man was brought to the emergency department for excruciating abdominal pain,vomiting and jaundice.He also had lower limb pitting edema and was hypotensive en route.Diagnosis:Congestive hepatopathy.Interventions:Intravenous furosemide and fluid restriction.Outcomes:The patient declined admission to the cardiology ward and discharged himself against medical advice after his condition was improved in the emergency department.Lessons:It is important to pay attention to acute abdominal pain induced by extraabdominal pathologies.In this case of acute decompensated congestive heart failure,early recognition of the cause makes a difference to the management.

Congenital disorder of glycosylation caused by mutation of ATP6AP1 gene (c.1036G>A) in a Chinese infant: A case report

BACKGROUND The ATP6AP1 gene coding for the accessory protein Ac45 of the vacuolar-type adenosine triphosphatases(V-ATPase)is located on chromosome Xq28.Defects in certain subunits or accessory subunits of the V-ATPase can lead to congenital disorders of glycosylation(CDG).CDG is a group of metabolic disorders in which defective protein and lipid glycosylation processes affect multiple tissues and organs.Therefore,the clinical presentation of patients with ATP6AP1-CDG varies widely.In this report,we present a case of ATP6AP1-CDG in a Chinese infant,with clinical features and genotype.CASE SUMMARY An 8-mo-old boy was admitted to our hospital because unexplained hepatosplenomegaly and elevated transaminases that had been noted while he was being treated for a cough at a local hospital.A post-admission examination at our hospital revealed abnormalities in the infant’s liver,brain,and immune system.Trio-based whole exome gene analysis identified a hemizygous pathogenic mutation c.1036G>A(p.E346K)in exon 9 of the ATP6AP1 gene.This variant of the ATP6AP1 gene has not been reported in East Asian countries until now.CONCLUSION Based on the infant’s clinical manifestations and the results of genetic detection,he was clearly diagnosed with ATP6AP1-CDG.The clinical manifestations of children with CDG vary widely.Genetic testing analysis helps in the clinical diagnosis of children with CDG.

Acute and chronic hepatobiliary manifestations of sickle cell disease: A review

Sickle cell disease(SCD) is a common hemoglobinopathy which can affect multiple organ systems in the body. Within the digestive tract, the hepatobiliary system is most commonly affected in SCD. The manifestations range from benign hyperbilirubinemia to overt liver failure, with the spectrum of acute clinical presentations often referred to as "sickle cell hepatopathy". This is an umbrella term referring to liver dysfunction and hyperbilirubinemia due to intrahepatic sickling process during SCD crisis leading to ischemia, sequestration and cholestasis. In this review, we detail the pathophysiology, clinical presentation and biochemical features of various acute and chronic hepatobiliary manifestations of SCD and present and evaluate existing evidence with regards to management of this disease process. We also discuss recent advances and controversies such as the role of liver transplantation in sickle cell hepatopathy and highlight important questions in this field which would require further research. Our aim with this review is to help increase the understanding, aid in early diagnosis and improve management of this important disease process.

Hepatic Kaposi sarcoma: A case report and review of the literature

Kaposi sarcoma(KS) is an aggressive cancer caused by human herpesvirus-8, primarily seen in immunocompromised patients. As opposed to the well-described cutaneous manifestations and pulmonary complications of KS, hepatic KS is rarely reported before death as most patients with hepatic KS do not manifest symptoms or evidence of liver injury. In patients with acquired immune deficiency syndrome, hepatic involvement of KS is present in 12%-24% of the population on incidental imaging and in approximately 35% of patients with cutaneous KS if an autopsy was completed after their death. Patients with clinically significant hepatic injury due to hepatic KS usually have an aggressive course of disease with hepatic failure often progressing to multi-organ failure and death. Here we report an unusual presentation of acute liver injury due to hepatic KS and briefly review the published literature on hepatic KS.

Gravity assistance enables liver stiffness measurements to detect liver fibrosis under congestive circumstances

BACKGROUND As survival has been prolonged owing to surgical and medical improvements,liver failure has become a prognostic determinant in patients with congestive heart diseases.Congestive hepatopathy,an abnormal state of the liver as a result of congestion,insidiously proceed toward end-stage liver disease without effective biomarkers evaluating pathological progression.Regular measurements of shear wave elastography cannot qualify liver fibrosis,which is a prognosticator in any type of chronic liver disease,in cases of congestion because congestion makes the liver stiff without fibrosis.We hypothesized that the effects of congestion and fibrosis on liver stiffness can be dissociated by inducing architectural deformation of the liver to expose structural rigidity.To establish a strategy measuring liver stiffness as a reflection of architectural rigidity under congestion.METHODS Two-dimensional shear wave elastography(2dSWE)was measured in the supine(Sp)and left decubitus(Ld)positions in 298 consecutive cases as they were subjected to an ultrasound study for various liver diseases.Regions of interest were placed at twelve sites,and the median and robust coefficient of variation were calculated.Numerical data were compared using the Mann-Whitney U or Kruskal-Wallis test followed by Dunn's post-hoc multiple comparisons.The inferior vena cava(IVC)diameters at different body positions were compared using the Wilcoxon matched pairs signed rank test.The number of cases with cardiothoracic ratios greater than or not greater than 50%was compared using Fisher’s exact test.A correlation of 2dSWE between different body positions was evaluated by calculating Spearman correlation coefficients.RESULTS The IVC diameter was significantly reduced in Ld in subjects with higher 2dSWE values in Ld(LdSWE)than in Sp(SpSWE)(P=0.007,(average±SD)13.9±3.6 vs 13.1±3.4 mm)but not in those with lower LdSWE values(P=0.32,13.3±3.5 vs 13.0±3.5 mm).In 81 subjects,SpSWE was increased or decreased in Ld beyond the magnitude of robust coefficient of variation,which suggests that body postural changes induced an alteration of liver stiffness significantly larger than the technical dispersion.Among these subjects,all 37 with normal SpSWE had a higher LdSWE than SpSWE(Normal-to-Hard,SpSWE-LdSWE(Δ2dSWE):(minimum-maximum)-0.74--0.08 m/sec),whereas in 44 residual subjects with abnormal SpSWE,LdSWE was higher in 27 subjects(Hard-to-Hard,-0.74--0.05 m/sec)and lower in 17 subjects(Hard-to-Soft,0.04-0.52 m/sec)than SpSWE.SpSWE was significantly correlated withΔ2dSWE only in Hard-to-Soft(P<0.0001).Δ2dSWE was larger in each lobe than in the entire liver.When Hard-to-Hard and Hard-to-Soft values were examined for each lobe,fibrosis-4 or platelet counts were significantly higher or lower only for Hard-to-Soft vs Normal-to-Hard cases.CONCLUSION Gravity alters the hepatic architecture during body postural changes,causing outflow blockage in hepatic veins.A rigid liver is resistant to structural deformation.Stiff-liver softening in the Ld position suggests a fibrous liver.

Cardiac Syndromes in Liver Disease:A Clinical Conundrum

Understanding the interaction between the heart and liver is pivotal for managing patients in whom both organs are affected.Studies have shown that cardio-hepatic interactions are bidirectional and that their identification,assessment,and treatment remain challenging.Congestive hepatopathy is a condition that develops in the setting of long-standing systemic venous congestion.If left untreated,congestive hepatopathy may lead to hepatic fibrosis.Acute cardiogenic liver injury develops as a combination of venous stasis and sudden arterial hypoperfusion due to cardiac,circulatory,or pulmonary failure.The treatment of both conditions should be directed toward optimizing the cardiac substrate.Hyperdynamic syndrome may develop in patients with advanced liver disease and lead to multiorgan failure.Cirrhotic cardiomyopathy or abnormalities in pulmonary vasculature,such as hepatopulmonary syndrome and portopulmonary hypertension may also develop.Each complication has unique treatment challenges and implications for liver transplantation.The presence of atrial fibrillation and atherosclerosis in liver disease brings another layer of complexity,particularly in terms of anticoagulation and statin use.This article provides an overview of cardiac syndromes in liver disease,focusing on current treatment options and future perspectives.