Polycythemia – Differential Diagnosis

Diagnostic flow chart. EPO, erythropoietin; R-L, right-to-left; ODC, oxygen dissociation curve; O2, oxygen; P. vera, polycythemia vera; CO, carbon monoxide.

Diagnostic flow chart from organ perspective. EPO, erythropoietin.

Mechanisms of increaseased erythropoietin (EPO) production. About 90% of Epo is produced by oxygen-sensing peritubular epithelial cells in the kidney. The remaining 10% is synthesized by liver hepatocytes. Under normoxic conditions, the transcription factor, hypoxia-inducible factor (HIF-1alpha) is hydroxylated at proline residues by prolyl-hydroxylase enzymes (PHD) degraded by proteasomes. The hydroxylated HIF-1α is recognized by von Hippel-Lindau (VHL), which is part of an E3 ubiquitin ligase complex, VHL-Elongin BC-CUL2 (VBC) complex. The VBC complex transfers ubiquitin and the ubiquitinated HIF-1α is transported to the proteasome for degradation. Under hypoxic condition (right panel), the enzymatic activity of PHD is decreased because of insufficient oxygen (O2). The un-hydroxylated HIF-1α is not recognized by VHL, and remain un-ubiquitinated. The un-ubiquitinated HIF-1α translocates from cytoplasm into nucleus, and heterodimerizes with HIF-beta. The HIF-1α/HIF-beta dimer binds hypoxic responsive element (HRE) DNA sequence and recruits p300/CBP to activate transcription of genes such as EPOVEGFA, and SLC2A1