Peter Ott

Polish Archives of Internal Medicine is an international, peer-reviewed, online-only periodical issued monthly in English as an official journal of the Polish Society of Internal Medicine. The journal is designed to publish articles related to all aspects of internal medicine, both clinical and basic science, provided they have practical implications.

Background and Purpose: Methanobactins are peptides with high copper affinity and potential to treat Wilson disease. We examined how two methanobactins (ARBM101 and MB‐OB3b) affected copper handling in the LPP Atp7b ^−/− Wilson disease rat model, compared to penicillamine or saline, by ⁶⁴ Cu positron emission tomography/magnetic resonance imaging. Heterozygotes served as controls. Experimental Approach: ⁶⁴ Cu was administered i.v. to 19 LPP and four control rats. A baseline scan was performed 1 h later. LPP rats received one dose of saline, penicillamine, MB‐OB3b or ARBM101 i.p. ( t = 100 min), followed by a 90‐min scan and a final scan at t = 24 h. Controls followed identical procedures without intervention. ⁶⁴ Cu levels were evaluated as % injected dose (%ID) in the liver, kidney and ‘abdominal‐pelvic region’ (intestines and other non‐hepatic, non‐renal organs). Key Results: At baseline, hepatic %ID was ≈50% higher in LPP rats than in controls. Intraintestinal ⁶⁴ Cu activity, indicating biliary excretion, was present in controls and absent in LPP rats. After methanobactin injection (but not saline or penicillamine), ⁶⁴ Cu appeared in the small intestines of LPP rats within 10–15 min. Hepatic %ID increased over 24 h in saline‐, penicillamine‐ and MB‐OB3b‐injected rats but decreased in control rats. ARBM101 almost normalised hepatic ⁶⁴ Cu at 24 h. Conclusions and Implications: A single i.p. methanobactin dose restored biliary copper excretion in LPP rats. The effect was more pronounced with ARBM101 than with MB‐OB3b. Non‐ATP7B transporters must be involved because ATP7B is absent in LPP rats. Methanobactin may have therapeutic potential in Wilson disease.

Elevated arterial ammonia is associated with several complications of liver disease as it predicts mortality for in-patients and decompensation, hospitalization and death in out-patients with cirrhosis. In this review, our aim was to estimate how the individual organs contribute to arterial ammonia based on published data from human studies. The brain removes ammonia from arterial blood in a concentration-dependent fashion. Ammonia that is released from the gut to portal blood is mainly from metabolism of glutamine in the enterocytes using this as a source of energy. Ammonia produced by bacterial metabolism of urea and proteins only partially reach portal blood and is likely recycled into bacterial proteins. In general, the liver efficiently removes ammonia from arterial or portal blood in proportion to the delivered concentration. As a result,– and in some contrast to conventional wisdom–, the hepato-splanchnic region only contributes marginally to arterial ammonia; even during a simulated upper GI bleed. The only exception is acute liver failure where hepatocyte necrosis allows large quantities of portal ammonia to pass. The kidneys release ammonia from glutamine metabolism into systemic blood. The renal ammonia release increases during a simulated upper GI bleed or hypokalemia where it becomes a major source of elevated arterial ammonia. In the resting state, muscles remove ammonia in a concentration-dependent manner and muscles are the primary ammonia lowering organ in most situations with elevated arterial ammonia. During strenuous exercise, muscles produce large amounts of ammonia into systemic blood. Thus, the complete pattern of ammonia metabolism is very dynamic and illustrates the difficulties in designing ammonia lowering therapies.

Urea synthesis is an irreversible, essential for maintenance of health and life, and highly regulated liver function with a very high capacity for production of the end-product urea-nitrogen. The set-point of urea synthesis in relation to its overall substrate, the prevailing blood concentration of L-α-amino acids, contributes to determine whole-body nitrogen balance and the size and composition of the plasma free amino acid pool. Ammonia is definitively eliminated from the body by urea synthesis. Ammonia is released by all tissues as part of their nitrogen metabolism and accumulation of ammonia to supranormal levels is toxic, particularly to the brain where it gives rise to the devastating complication to liver diseases, hepatic encephalopathy. The first line ammonia scavenging has an efficiently high clearance several times over hepatic blood flow and close to cardiac output, under normal conditions securing rapid neutralization of ammonia by synthesis of amino acids and glutamine. This scavenging has a much lower capacity than urea synthesis. Maintenance of the scavenging system, therefore, relies on subsequent definitive depletion and elimination of amino- and amide-nitrogen to urea-nitrogen. In liver diseases, the capacity for urea synthesis is deficient due to reduced functional liver mass and dysregulation, which eventually delays the scavenging so that ammonia overflows. Considering the key role of ammonia in hepatic encephalopathy, this indirect relationship implies that deficient urea synthesis is a prerequisite for development of hyperammonemia and hepatic encephalopathy. This is in accordance with the definition of hepatic encephalopathy as being caused by liver insufficiency, where the insufficiency more specifically likely is deficiency of the urea synthesis.

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Background: Ammonia is implicated in hepatic encephalopathy (HE) and prognostic in cirrhosis. Venous ammonia concentration, yielding similar correlation with HE grades as arterial, has become the preferred practise but comparative data are limited. Aim: To quantify effect of sampling site on ammonia concentration in healthy persons and patients with cirrhosis. Methods: Ammonia concentrations were measured by arterial and femoral venous blood sampling in ten healthy men and ten male patients with cirrhosis before and during hyperammonaemia induced by ammonia infusion. Cubital vein samples were included during the infusion. Results: At baseline, arterial-venous concentration gaps were similar (p = 0.15) in healthy persons [14 (10–19) and 8 (4–12) µmol/L] and patients with cirrhosis [53 (32–74) and 40 (23–57) µmol/L]. Ammonia infusion increased arterial-venous concentration gaps in both groups [115 (97–133) and 61 (31–90) vs. 175 (123–227) and 134 (65–203) µmol/L]. Mean ammonia concentration difference between groups during hyperammonaemia was 72 (42–103) µmol/L (p < 0.001) and independent of sampling site. Cubital and femoral vein concentrations were comparable (p = 0.26). In cirrhosis, calculated upper limit normal values (ULN) were comparable for arterial and venous blood at baseline [2.0 (1.2–2.8) and 2.1 (1.2–3.0), p = 0.74] and during hyperammonaemia [6.7 (4.7–8.7) and 6.2 (4.4– 8.1), p = 0.44]. Conclusions: We found clinically meaningful intra-individual arterial-venous concentration gaps in both healthy persons and patients with cirrhosis at any ammonia concentration. Inter-group concentration differences after induced hyperammonaemia were relatively constant across sampling sites which supports clinical use of venous sampling. ULN-normalised ammonia concentrations were valid for both arterial and venous sampling.

Copper transporting P-type (P_1B-1-) ATPases are essential for cellular homeostasis. Nonetheless, the E1-E1P-E2P-E2 states mechanism of P_1B-1-ATPases remains poorly understood. In particular, the role of the intrinsic metal binding domains (MBDs) is enigmatic. Here, four cryo-EM structures and molecular dynamics simulations of a P_1B-1-ATPase are combined to reveal that in many eukaryotes the MBD immediately prior to the ATPase core, MBD⁻¹, serves a structural role, remodeling the ion-uptake region. In contrast, the MBD prior to MBD⁻¹, MBD⁻², likely assists in copper delivery to the ATPase core. Invariant Tyr, Asn and Ser residues in the transmembrane domain assist in positioning sulfur-providing copper-binding amino acids, allowing for copper uptake, binding and release. As such, our findings unify previously conflicting data on the transport and regulation of P_1B-1-ATPases. The results are critical for a fundamental understanding of cellular copper homeostasis and for comprehension of the molecular bases of P_1B-1-disorders and ongoing clinical trials.