Uncommon Alliance: Portal Hypertension in Diabetic Nephropathy-Related Nephrotic Syndrome with a Healthy Liver

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Uncommon Alliance: Portal Hypertension in Diabetic Nephropathy-Related Nephrotic Syndrome with a Healthy Liver
Erick Ivan
Marrero Santiago
Andres Aranda - G. de Quevedo dr.andresaranda@gmail.com Universidad Autonoma de Guadalajara / Hospital General de Occidente School of Medicine / Nephrology Department Zapopan
Linda Giovanna Ruiz - Fabian dra.giovannaruiz@gmail.com Universidad Autonoma de Guadalajara School of Medicine Zapopan
Hector Enrique Garcia - Bejarano garciabejarano.garcia@gmail.com Hospital General de Occidente Nephrology Department Zapopan
Faviola Marie Negron - Alick faviola.negron@edu.uag.mx Universidad Autonoma de Guadalajara School of Medicine Zapopan
David Pagan - Maldonado david.pagan@edu.uag.mx Universidad Autonoma de Guadalajara School of Medicine Zapopan
Cristian Xavier Rivera - Benitez cristian.rivera@edu.uag.mx Universidad Autonoma de Guadalajara School of Medicine Zapopan
Valeria Mora - Castillo vmora@edu.uag.mx Universidad Autonoma de Guadalajara School of Medicine Zapopan
Kashif Adil Ahmad Kashif@edu.uag.mx Universidad Autonoma de Guadalajara School of Medicine Zapopan
Miranda Robledo - Amezcua miranda.robledo@edu.uag.mx Universidad Autonoma de Guadalajara School of Medicine Zapopan
Alejandra Mariel Franco - Martinez alejandram.franco@edu.uag.mx Universidad Autonoma de Guadalajara School of Medicine Zapopan
Enid Duran - Gonzalez enid.duran@edu.uag.mx Universidad Autonoma de Guadalajara School of Medicine Zapopan
Simon Quetzalcoalt Rodriguez - Lara simon.rodriguez@edu.uag.mx Universidad Autonoma de Guadalajara School of Medicine Zapopan
Saul Palomino - Ayala saulpalomina@hotmail.com Hospital General de Occidente Gastroenterology department Zapopan
Lucia Elizabeth Alvarez - Palazuelos lucia.palazuelos@edu.uag.mx Universidad Autonoma de Guadalajara School of Medicine Zapopan
Miguel Alejandro Davalos - Benitez miguela.davalos@edu.uag.mx Universidad Autonoma de Guadalajara School of Medicine Zapopan
Diabetic nephropathy is a known cause of nephrotic syndrome, which can lead to a prothrombotic state. Patients with diabetes are also at increased risk of developing thrombosis. Although non-alcoholic liver disease is common in these patients, even individuals with a healthy liver can develop portal thrombosis. Portal vein thrombosis most commonly occurs in non-cirrhotic patients, often extending into the splenic and mesenteric veins, resulting in pre-hepatic venous thrombosis. This condition leads to portal vein hypertension, manifesting as splenomegaly, upper gastrointestinal bleeding, or esophageal bleeding, even when liver function tests appear normal and the liver is healthy.

Case Study

We present a 46-year-old female from a major city in Mexico. She has had poorly controlled type 2 diabetes mellitus (DM) and high blood pressure for 12 years, with no prior chronic kidney disease (CKD) diagnosis. In February 2022, following a course of antibiotics for a urinary tract infection caused by Proteus mirabilis, she developed progressive bilateral bimalleolar edema that later progressed to ascites. In March 2022, the patient began experiencing melena. An upper endoscopy (image 1) revealed four varicose cords measuring less than 5 mm in the mucosa of the distal third of the esophagus, extending into the middle third. The gastric mucosa showed subepithelial hemorrhage, but no erosions. These findings indicated the presence of esophageal varices without high-risk stigmata, along with severe portal hypertensive gastropathy.

Due to the clinical presentation of fluid overload, ascites, and upper gastrointestinal bleeding attributed to portal hypertension, along with poorly controlled type 2 diabetes mellitus, she received a clinical diagnosis of chronic hepatic cirrhosis caused by non-alcoholic fatty liver disease (NAFLD). Ultrasound revealed an enlarged liver with normal echogenicity, no focal or diffuse lesions, no biliary dilatation, and a tortuous and irregular portal vein with portosystemic collaterals. The spleen was enlarged, but the splenic vein was not assessed. Kidney dimensions were normal. She was treated for esophageal varices related to cirrhosis with spironolactone, furosemide, and propranolol but continued to experience a weight gain of over 20 kg due to fluid overload.

Referral to the nephrology service came after the patient's blood urea and creatinine levels increased from 1.2 mg/dl March 22 to 2.35 mg/dl January 23, likely due to a type 2 hepatorenal syndrome and uncontrolled hypertension. The patient had ambulatory blood pressure over 160/90 and normal liver function tests but exhibited low plasma albumin levels and nephrotic range proteinuria. Medication adjustments were made for decongestion, and further tests, including a hepatic and biliary ultrasound, showed a normal liver, but also a patent portal vein with cavernomatous degeneration (image 2), adequate flow in suprahepatic veins, and portal vein diameter and velocities. The spleen and vein were normal. Triphasic computed tomography of the liver confirmed normal liver appearance, collateral vessel presence, and recanalization from the right to the left portal vein due to cavernomatous degeneration, suggestive of portal hypertension and findings of hypertensive gastropathy.

Hospitalization was initiated to investigate a possible nephrotic syndrome and rule out secondary membranous nephropathy. Serological tests for ANA, Anti-DNA, HBV, HCV, and HIV were negative. C3 and C4 levels were normal, but the patient couldn't afford Anti-PLA2R testing. Ca125 levels were high at 239.8 (table 1). Cytologic evaluation of ascitic pleural fluids revealed no malignant cells. A repeat upper endoscopy found no esophageal varices, but the stomach mucosa exhibited subepithelial hemorrhage, indicative of portal hypertension. A kidney biopsy (image 4) demonstrated glomerular changes consistent with Diabetic Nephropathy Class IV (RPS), which was surprising given the prior lack of CKD diagnosis.

In retrospect, the patient was diagnosed with portal hypertension due to portal vein thrombosis secondary to a nephrotic syndrome caused by a poorly controlled type 2 diabetes mellitus. As the patient's condition improved, better portal circulation resulting from thrombus degeneration, endoscopic findings also indicated improvement in esophageal varices (image 1,3). Nonetheless, the patient's clinical complexity, including portal hemodynamic changes and a severely damaged kidney, accelerated her CKD progression. Currently, she is undergoing optimized medical treatment for advanced CKD, including dual tubular blockade, glycemic control, antihypertensive therapy, and preparation for peritoneal dialysis. Her clinical presentation suggests fluid overload primarily in the third space and extracellular matrix, with recurrent ascites and limb edema, making her an excellent candidate for peritoneal dialysis and a potential renal transplant in the near future. This case presented a challenge due to its clinical complexity, and thanks to the interdisciplinary efforts of the gastroenterology and nephrology teams, the correct etiology was determined. It underscores the importance of investigating the precise etiology of chronic diseases and being alert to the potential coexistence of multiple pathologies, which can lead to the development of additional diseases.

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