Advanced liver disease complicated by hepatopulmonary syndrome is a recognized complication of Gaucher disease. Macrophage-targeted, recombinant enzyme replacement therapy is effective in reversing ...clinical manifestations attributed to the accumulation of glycolipid-laden macrophages but it is not known whether advanced fibrotic features of the disease can be ameliorated. We describe a splenectomized patient with Gaucher disease who developed massive hepatomegaly, cirrhosis of the liver and life-threatening hepatopulmonary syndrome. Treatment with Imiglucerase enzyme replacement therapy resulted in dramatic reversal of hepatopulmonary syndrome and liver disease. Our report suggests that Gaucher disease pathology involving advanced fibrosis and life-threatening complications can be reversed by imiglucerase enzyme therapy. SYNOPSISEffect of imiglucerase enzyme replacement therapy on Hepatopulmonary Syndrome in Gaucher Disease.
Metabolic liver disease Schilsky, Michael L; Mistry, Pramod
Current opinion in gastroenterology
17, Številka:
3
Journal Article
Recenzirano
The discovery of novel metabolic pathways and the genetic basis for diseases of the liver continues to yield new insights into the pathogenesis of inherited metabolic diseases of the liver, whereas ...the application of new technologies to their treatment continues to advance therapeutic options. This review of selected articles covers a wide range of subjects, from the identification of novel proteins and transport pathways to disease diagnosis and treatment of acute liver failure. Four selected topics, Wilson disease, hemochromatosis and iron overload disorders, α-1 antitrypsin disease, and exciting new therapeutic options for lysosomal storage diseases are the focus of this review.
Inherited metabolic disease Schilsky, Michael L; Mistry, Pramod
Current opinion in gastroenterology
16, Številka:
3
Journal Article
Recenzirano
This review focuses on two genetic disorders of metal metabolism, genetic hemochromatosis and Wilson disease, and on the most common lysosomal storage disorder, Gaucher disease, for which recombinant ...enzyme replacement therapy is available. The discovery of the genes for these disorders has led to an explosion of new information about the function of these gene products and the identification of other proteins involved in their metabolism. These discoveries have altered our current diagnostic and therapeutic approaches to these disorders and have furthered our understanding of disease pathophysiology. New modalities being developed for future use include cell transplant and genetic replacement therapies.
BACKGROUNDThe most common lysosomal storage disorder is Gaucher disease (GD). It is a deficiency of lysosomal glucocerebrosidase (GBA) due to biallelic mutations in the GBA gene, characterized by the ...deposition of glucocerebroside in macrophage-monocyte system cells. The report targets clinical phenotypes of GD in order to correlate them with GBA gene mutations, as well as to identify GBA gene mutation in patients in Montenegro that are diagnosed with GD. CASES SUMMARYFive patients (4 male, 1 female) of type 1 GD (GD1) are reported. The age at diagnosis ranged from 7 to 40. Patients experienced delays of 1-12 years in diagnosis after the original onset of symptoms. The most common mode of presentation was a variable degree of splenomegaly and thrombocytopenia, while other symptoms included bone pain, hepatomegaly, abdominal pain and fatigue. Osteopenia was present in a majority of the patients: 4/5. All patients were found to have an asymptomatic Erlenmeyer flask deformity of the distal femur. On enzyme replacement therapy (ERT), the hematological and visceral parameters showed significant improvement, but no significant progression in bone mineral density was noticed. GBA gene sequencing revealed homozygosity for the N370S mutation in one patient. The genotypes of the other patients were N370S/55bp deletion, N370S/D409H (2 patients), and H255Q/N370S (1 patient). CONCLUSIONThe phenotypes of the GD1 encountered in Montenegro were severe but all responded well to ERT.
BACKGROUNDGaucher disease type 1 (GD1) is a lysosomal storage disease rarely resulting in end stage pulmonary hypertension (PH) and interstitial lung disease. There have only been two previous case ...reports of patients with GD1 receiving lung transplants. CASE PRESENTATIONWe report a case of successful bilateral sequential lung transplantation in a patient with end-stage GD1-related PH. Prior to transplant, the patient was on enzyme replacement therapy with imiglucerase and pulmonary vasodilator therapy with bosentan, sildenafil and epoprostenol. The patient had pre-transplant comorbidities of prior splenectomy and osteopenia. She underwent bilateral sequential lung transplantation with basiliximab, methylprednisolone and mycophenolate mofetil induction. Her explanted lungs demonstrated severe pulmonary arterial hypertensive changes, but no Gaucher cells. She was maintained on MMF, tacrolimus, prednisone, imiglucerase and warfarin post-transplant. Her post-transplant course was complicated by hemorrhagic shock, prolonged support with extracorporeal membrane oxygenation, and acute renal failure requiring dialysis. Despite these complications, the patient was discharged and is doing well nine months post-transplantation. CONCLUSIONSThis is one of only three reported cases of lung transplantation in patients with GD1. Each case has involved previously splenectomised, female patients with GD1. This is the first to report transplantation in a patient with severe PH and no pulmonary parenchymal disease. As evidenced in our patient, long term treatment with imiglucerase may eliminate the Gaucher cells in the lungs. The PH in these patients is most consistent with pulmonary arterial hypertension, raising the question of whether this should be reclassified as WHO Group 1 PH.
Wilson disease is a disorder of copper metabolism due to defective intracellular copper transport in hepatocytes. The mutant gene in Wilson disease encodes a copper-transporting ATPase known as ATP7B ...that is mainly expressed in hepatocytes. Mutations that cause reduced function or absence of ATP7B reduce hepatic biliary copper excretion and cause hepatic copper accumulation. Nephrolithiasis may be found in some patients with Wilson disease. This is most likely present in patients with tubular defects in acidification or resultant changes in the urinary excretion of substrates that augment stone formation. In the setting of either acute or severe chronic liver failure due to Wilson disease, hepatorenal syndrome may develop. This entity is defined by the development of oliguria in association with reduced renal clearance and a low urine sodium excretion of ‹10 mEq/l that is unresponsive to volume expansion. Patients with acute liver failure due to Wilson disease have a higher incidence of renal dysfunction compared to other etiologies of liver failure. Renal injury may occur not only from copper, but also from some of the treatments for Wilson disease. Most commonly, the copper-chelating drug, d-penicillamine, may cause acute or later-onset renal toxicity. A syndrome with lupus nephritis may occur early on, associated with the appearance of cellular elements in the urinary sediment and renal injury. Proteinuria of varying degrees may occur even years following the initiation of therapy with d-penicillamine. Within the first 2 years of therapy, low-molecular-weight proteins are found in the urine, suggesting tubular injury.
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